Inhibitor of indoleamine-2,3-dioxygenase (ido)

ABSTRACT

The present disclosure provides compounds of Formula (I). The compounds described herein may be useful in treating a disease associated with IDO, for example, cancer or an infectious disease (e.g., viral or bacterial infectious diseases). Also, provided in the present disclosure are pharmaceutical compositions, kits, methods, and uses including or using a compound described herein.

RELATED APPLICATIONS

This application is the U.S. national phase of International ApplicationNo. PCT/US2017/017063, filed Feb. 8, 2017, which claims priority under35 U.S.C. § 119(e) to U.S. Provisional Patent Applications, U.S. Ser.No. 62/293,219, filed Feb. 9, 2016, and U.S. Ser. No. 62/362,875, filedJul. 15, 2016, the entire contents of each of which is incorporatedherein by reference.

BACKGROUND OF THE INVENTION

Indoleamine 2,3-dioxygenase (IDO), for example, Indoleamine2,3-dioxygenase 1 (IDO1), is a family of heme-containing enzymes thatcatalyzes the degradation of the essential amino acid L-tryptophan toN-formylkynurenine. It plays an important role in the initial and ratelimiting step in the breakdown of tryptophan.

It has been reported that IDO (e.g., IDO1), an enzyme induced by IFNγ,is one of the central regulators of immune responses in variousphysiological and pathological settings. IDO causes immunosuppressionthrough breakdown of tryptophan in the tumor microenvironment. (Selvanet al., Curr. Cancer Drug Targets, 2015; Baren and Eynde CancerImmunology Research, 2015). Overexpression of IDO was observed invarious tumors (e.g., colorectal cancer, ovarian cancer, and breastcancer), which is thought to enable tumor cells escape fromimmunosurveillance. [Godin-Ethier et al., Clinical Cancer Research, 2011Nov. 15; 17 (22): 6985-91]. It was also found that Treg cells regulatesIDO mediated tryptophan catabolism in dendritic cells. (Fallarino, et.al. Nature Immunology 2003). In addition, IDO has been associated withother diseases such as viral infections and Alzheimer's. Accordingly,IDO is a promising target in cancer, e.g., cancer immune-therapy, aswell as in other diseases such as infectious diseases and Alzheimer's.

SUMMARY OF THE INVENTION

The present disclosure provides compounds, such as compounds of Formula(I), which inhibit IDO such as IDO1 and hence, inhibit tryptophancatabolism and reduction of kynurenine in the tumor microenvironment andsurrounding lymph nodes. The compounds described herein may be useful intreating proliferative diseases such as cancer (e.g., non-small celllung cancer, small cell lung cancer, breast cancer, prostate cancer,ovarian cancer, bladder cancer, head and neck cancer, renal cellcarcinoma, pancreatic cancer, brain cancer, cancers of thegastrointestinal tract, liver cancer, leukemia, lymphoma, melanoma,multiple myeloma, Ewing's sarcoma, osteosarcoma, and neuroblastoma) andinfectious diseases such as viral or bacterial infectious diseases(e.g., hepatitis and HIV). Also provided are pharmaceuticalcompositions, kits, methods, and uses of any of the compounds describedherein.

In one aspect, the present disclosure provides compounds of Formula (I):

or pharmaceutically acceptable salts, wherein W is —O—, —S—, or a bond;Q is —C(═O)NH— or a bond; Y is —CR⁸═ or —N═, as valency permits. Inaddition,

R¹ is —C(═O)OH, —C(═O)OR¹⁰, substituted or unsubstituted heterocyclyl,substituted or unsubstituted heteroaryl, —NHSO₂R⁹, —C(═O)NHSO₂R⁹,—C(═O)NHC(═O)OR¹⁰, or —SO₂NHC(═O)R¹⁰;

R² and R³ are each independently hydrogen, halogen, substituted orunsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₁-C₆ alkoxy, orR² and R³ are joined to form a substituted or unsubstituted 3- to8-membered carbocyclic ring, or substituted or unsubstituted 3- to8-membered heterocyclic ring;

R⁴ and R⁵ are each independently hydrogen, substituted or unsubstitutedC₁-C₆ alkyl, substituted or unsubstituted C₂-C₆ alkenyl, substituted orunsubstituted C₅-C₈ cycloalkenyl, substituted or unsubstituted C₂-C₁₀alkynyl, substituted or unsubstituted aryl, substituted or unsubstitutedC₁-C₆ alkoxy, substituted or unsubstituted C₃-C₈ cycloalkyl, substitutedor unsubstituted 3- to 12-membered heterocyclyl (e.g.,heterocycloalkyl), substituted or unsubstituted 5- to 6-memberedmonocyclic heteroaryl, substituted or unsubstituted 8- to 10-memberedbicyclic heteroaryl, or arylsulfonyl; or R⁴ and R⁵ are joined togetherwith the N they are attached to to form optionally substituted,heterocyclyl, which may be monocyclic or bicyclic.

R⁶ is substituted or unsubstituted C₁-C₆ alkyl, substituted orunsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₂-C₆alkenyl, substituted or unsubstituted C₂-C₆ alkynyl, or substituted orunsubstituted C₅-C₈ cycloalkenyl, substituted or unsubstituted aryl,substituted or unsubstituted 4- to 7-membered monocyclic heterocyclyl(e.g., heterocycloalkyl), substituted or unsubstituted 7- to 10-memberedbicyclic heterocyclyl, substituted or unsubstituted 5- to 6-memberedmonocyclic heteroaryl, substituted or unsubstituted 8- to 10-memberedbicyclic heteroaryl, substituted or unsubstituted C₁-C₆ alkoxy,substituted or unsubstituted aryloxy, or —C(═O)R⁷;

R⁷ is hydrogen, substituted or unsubstituted C₁-C₆ alkyl, or substitutedor unsubstituted aryl;

R⁸ is independently hydrogen, halogen, —CN, —OH, substituted orunsubstituted C₁-C₆ alkyl, or substituted or unsubstituted C₁-C₆ alkoxy;and

R⁹ and R¹⁰ are each independently hydrogen, or substituted orunsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₂-C₆ alkenyl;or a pharmaceutically acceptable salt, wherein R¹, R², R³, R⁴, R⁵, R⁶,R⁷, R⁸, R⁹, R¹⁰, Y, and Q are as defined herein.

In certain embodiments, R¹ is —C(═O)OH, substituted or unsubstitutedheterocyclyl, —NHSO₂R⁹, —C(═O)NHSO₂R⁹, —C(═O)NHC(═O)OR¹⁰, or—SO₂NHC(═O)R¹⁰.

In certain embodiments, R⁴ and R⁵ are each independently hydrogen,substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstitutedC₂-C₆ alkenyl, substituted or unsubstituted C₅-C₈ cycloalkenyl,substituted or unsubstituted C₂-C₁₀ alkynyl, substituted orunsubstituted aryl, substituted or unsubstituted C₁-C₆ alkoxy,substituted or unsubstituted C₃-C₈ cycloalkyl, substituted orunsubstituted 3- to 12-membered heterocyclyl (e.g., heterocycloalkyl),substituted or unsubstituted 5- to 6-membered monocyclic heteroaryl,substituted or unsubstituted 8- to 10-membered bicyclic heteroaryl,substituted or unsubstituted aryl, or arylsulfonyl.

In certain embodiments, a compound of Formula (I) is of Formula (II):

or a pharmaceutically acceptable salt, wherein R¹, R², R³, R⁴, R⁵, R⁶,Y, and Q are as described herein.

Exemplary compounds of Formula (II) include, but are not limited to:

and pharmaceutically acceptable salts.

In certain embodiments, a compound of Formula (I) is of Formula (III):

or a pharmaceutically acceptable salt, wherein R¹, R², R³, R⁴, R⁵, R⁶,Y, and Q are as defined herein.

Exemplary compounds of Formula (III) also include, but are not limitedto:

and pharmaceutically acceptable salts.

In certain embodiments, a compound of Formula (I) is of Formula (IV):

or a pharmaceutically acceptable salt, wherein R¹, R², R³, R⁴, R⁵, R⁶,Y, and Q are as defined herein.

Exemplary compounds of Formula (IV) include, but are not limited to:

and pharmaceutically acceptable salts.

In certain embodiments, a compound of Formula (I) is of Formula (V):

or a pharmaceutically acceptable salt, wherein R¹, R², R³, R⁴, R⁵, R⁶,W, and Y are as defined herein.

Exemplary compounds of Formula (V) include, but are not limited to:

and pharmaceutically acceptable salts.

In another aspect, the present disclosure provides pharmaceuticalcompositions including one or more of the compounds described herein,and a pharmaceutically acceptable excipient. In certain embodiments, thepharmaceutical compositions described herein include an effective amountof a compound described herein for inhibiting IDO and tryptophancatabolism resulting in reduced kynurenine level. An effective amountdescribed herein may be a therapeutically effective amount orprophylactically effective amount.

In yet another aspect, the present disclosure provides methods fortreating a disease associated with IDO (e.g., a cancer or an infectiousdisease), the method comprising administering to a subject in need ofthe treatment an effective amount of any of the pharmaceuticalcompositions described herein.

In certain embodiments, a target cancer include, but not limited to,non-small cell lung cancer, small cell lung cancer, breast cancer,prostate cancer, ovarian cancer, bladder cancer, head and neck cancer,renal cell carcinoma, pancreatic cancer, brain cancer, cancers of thegastrointestinal tract, liver cancer, leukemia, lymphoma, melanoma,multiple myeloma, Ewing's sarcoma, osteosarcoma, neuroblastoma.

In certain embodiments, the subject being treated is a mammal (e.g.,human or non-human mammal).

In certain embodiments, the present disclosure provides combined therapyof a cancer patient, using both an IDO inhibitory compound as describedherein and another anti-cancer therapy, which includes, but is notlimited to, an immunetherapy, a radiotherapy, surgery, a chemotherapy,and a cell therapy. In some examples, the other anti-cancer therapyinvolves the use of one or more anti-cancer agents.

Another aspect of the present disclosure relates to kits comprising acontainer with a compound, or pharmaceutical composition thereof, asdescribed herein. The kits described herein may include a single dose ormultiple doses of the compound or pharmaceutical composition. The kitsmay be useful in a method of the disclosure. In certain embodiments, thekit further includes instructions for using the compound orpharmaceutical composition.

In yet another aspect, the present disclosure provides compounds andpharmaceutical compositions described herein for use in treating aproliferative disease such as cancer as described herein and/or formanufacturing a medicament for use in treating the target disease.

The details of one or more embodiments of the disclosure are set forthherein. Other features, objects, and advantages of the disclosure willbe apparent from the Detailed Description, the Examples, and the Claims.

BRIEF DESCRIPTION OF THE DRAWINGS

Non-limiting embodiments of the present disclosure will be described byway of example with reference to the accompanying figures, which areschematic and are not intended to be drawn to scale. In the figures,each identical or nearly identical component illustrated is typicallyrepresented by a single numeral. For purposes of clarity, not everycomponent is labeled in every figure, nor is every component of eachembodiment of the invention shown where illustration is not necessary toallow those of ordinary skill in the art to understand the invention.

FIG. 1 is a chart showing the inhibition of kynurenine production inSKOV-3 cells by Compound 9 and INCB-24360.

FIG. 2 is a chart showing LPS-induced mouse plasma kynurenine levels inthe presence or absence of Compound 9.

FIG. 3 includes charts showing the reduction of kynurenine in humanwhole blood sample after compound treatment. Panel A: Percentageinhibition of kynurenine to tryptophan ratio by compound 84 and compoundINCB-24360, respectively, as a function of the concentration of eachcompound. Panel B: Percentage inhibition of kynurenine by compound 84and compound INCB-24360, respectively, as a function of theconcentration of each compound.

FIG. 4 is a chart showing IDO inhibitors increased the production ofIFN-gamma in the T cells and HeLa cells co-culture media, suggestingactivation of T cells by IDO inhibitor. EC₅₀ of INCB-24360 and compound120 in this assay were 41 nM and 9.1 nM, respectively.

DEFINITIONS

Definitions of specific functional groups and chemical terms aredescribed in more detail below. The chemical elements are identified inaccordance with the Periodic Table of the Elements, CAS version,Handbook of Chemistry and Physics, 75^(th) Ed., inside cover, andspecific functional groups are generally defined as described therein.Additionally, general principles of organic chemistry, as well asspecific functional moieties and reactivity, are described in ThomasSorrell, Organic Chemistry, University Science Books, Sausalito, 1999;Smith and March, March's Advanced Organic Chemistry, 5^(th) Edition,John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive OrganicTransformations, VCH Publishers, Inc., New York, 1989; and Carruthers,Some Modern Methods of Organic Synthesis, 3^(rd) Edition, CambridgeUniversity Press, Cambridge, 1987. The disclosure is not intended to belimited in any manner by the exemplary listing of substituents describedherein.

Compounds described herein can comprise one or more asymmetric centers,and thus can exist in various isomeric forms, e.g., enantiomers and/ordiastereomers. For example, the compounds described herein can be in theform of an individual enantiomer, diastereomer or geometric isomer, orcan be in the form of a mixture of stereoisomers, including racemicmixtures and mixtures enriched in one or more stereoisomer. Isomers canbe isolated from mixtures by methods known to those skilled in the art,including chiral high pressure liquid chromatography (HPLC) and theformation and crystallization of chiral salts; or preferred isomers canbe prepared by asymmetric syntheses. See, for example, Jacques et al.,Enantiomers, Racemates and Resolutions (Wiley Interscience, New York,1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistryof Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables ofResolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ.of Notre Dame Press, Notre Dame, Ind. 1972). The disclosure additionallyencompasses compounds described herein as individual isomerssubstantially free of other isomers, and alternatively, as mixtures ofvarious isomers.

When a range of values is listed, it is intended to encompass each valueand sub-range within the range. For example “C₁₋₆” is intended toencompass, C₁, C₂, C₃, C₄, C₅, C₆, C₁₋₆, C₁₋₅, C₁₋₄, C₁₋₃, C₁₋₂, C₂₋₆,C₂₋₅, C₂₋₄, C₂₋₃, C₃₋₆, C₃₋₅, C₃₋₄, C₄₋₆, C₄₋₅, and C₅₋₆.

The term “aliphatic” includes both saturated and unsaturated, straightchain (i.e., unbranched), branched, acyclic, cyclic, or polycyclicaliphatic hydrocarbons, which are optionally substituted with one ormore functional groups. As will be appreciated by one of ordinary skillin the art, “aliphatic” is intended herein to include, but is notlimited to, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, andcycloalkynyl moieties. Thus, the term “alkyl” includes straight,branched and cyclic alkyl groups. An analogous convention applies toother generic terms such as “alkenyl”, “alkynyl”, and the like.Furthermore, the terms “alkyl”, “alkenyl”, “alkynyl”, and the likeencompass both substituted and unsubstituted groups. In certainembodiments, “lower alkyl” is used to indicate those alkyl groups(cyclic, acyclic, substituted, unsubstituted, branched or unbranched)having 1-6 carbon atoms.

In certain embodiments, the alkyl, alkenyl, and alkynyl groups employedin the disclosure contain 1-20 aliphatic carbon atoms. In certain otherembodiments, the alkyl, alkenyl, and alkynyl groups employed in thedisclosure contain 1-10 aliphatic carbon atoms. In yet otherembodiments, the alkyl, alkenyl, and alkynyl groups employed in thedisclosure contain 1-8 aliphatic carbon atoms. In still otherembodiments, the alkyl, alkenyl, and alkynyl groups employed in thedisclosure contain 1-6 aliphatic carbon atoms. In yet other embodiments,the alkyl, alkenyl, and alkynyl groups employed in the disclosurecontain 1-4 carbon atoms. Illustrative aliphatic groups thus include,but are not limited to, for example, methyl, ethyl, n-propyl, isopropyl,cyclopropyl, —CH₂-cyclopropyl, vinyl, allyl, n-butyl, sec-butyl,isobutyl, tert-butyl, cyclobutyl, —CH₂-cyclobutyl, n-pentyl, sec-pentyl,isopentyl, tert-pentyl, cyclopentyl, —CH₂-cyclopentyl, n-hexyl,sec-hexyl, cyclohexyl, —CH₂-cyclohexyl moieties and the like, whichagain, may bear one or more substituents. Alkenyl groups include, butare not limited to, for example, ethenyl, propenyl, butenyl,1-methyl-2-buten-1-yl, and the like. Representative alkynyl groupsinclude, but are not limited to, ethynyl, 2-propynyl (propargyl),1-propynyl, and the like.

The term “alkyl” refers to a radical of a straight-chain or branchedsaturated hydrocarbon group having from 1 to 10 carbon atoms (“C₁₋₁₀alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms(“C₁₋₉ alkyl”). In some embodiments, an alkyl group has 1 to 8 carbonatoms (“C₁₋₈ alkyl”). In some embodiments, an alkyl group has 1 to 7carbon atoms (“C₁₋₇ alkyl”). In some embodiments, an alkyl group has 1to 6 carbon atoms (“C₁₋₆ alkyl”). In some embodiments, an alkyl grouphas 1 to 5 carbon atoms (“C₁₋₅ alkyl”). In some embodiments, an alkylgroup has 1 to 4 carbon atoms (“C₁₋₄ alkyl”). In some embodiments, analkyl group has 1 to 3 carbon atoms (“C₁₋₃ alkyl”). In some embodiments,an alkyl group has 1 to 2 carbon atoms (“C₁₋₂ alkyl”). In someembodiments, an alkyl group has 1 carbon atom (“C₁ alkyl”). In someembodiments, an alkyl group has 2 to 6 carbon atoms (“C₂₋₆ alkyl”).Examples of C₁₋₆ alkyl groups include methyl (C₁), ethyl (C₂), propyl(C₃) (e.g., n-propyl, isopropyl), butyl (C₄) (e.g., n-butyl, tert-butyl,sec-butyl, iso-butyl), pentyl (C₅) (e.g., n-pentyl, 3-pentanyl, amyl,neopentyl, 3-methyl-2-butanyl, tertiary amyl), and hexyl (C₆) (e.g.,n-hexyl). Additional examples of alkyl groups include n-heptyl (C₇),n-octyl (C₈), and the like. Unless otherwise specified, each instance ofan alkyl group is independently unsubstituted (an “unsubstituted alkyl”)or substituted (a “substituted alkyl”) with one or more substituents(e.g., halogen, such as F). In certain embodiments, the alkyl group isan unsubstituted C₁₋₁₀ alkyl (such as unsubstituted C₁₋₆ alkyl, e.g.,—CH₃). In certain embodiments, the alkyl group is a substituted C₁₋₁₀alkyl (such as substituted C₁₋₆ alkyl, e.g., —CF₃).

“Alkenyl” refers to a radical of a straight-chain or branchedhydrocarbon group having from 2 to 20 carbon atoms, one or morecarbon-carbon double bonds, and no triple bonds (“C₂₋₂₀ alkenyl”). Insome embodiments, an alkenyl group has 2 to 10 carbon atoms (“C₂₋₁₀alkenyl”). In some embodiments, an alkenyl group has 2 to 9 carbon atoms(“C₂₋₉ alkenyl”). In some embodiments, an alkenyl group has 2 to 8carbon atoms (“C₂₋₈ alkenyl”). In some embodiments, an alkenyl group has2 to 7 carbon atoms (“C₂₋₇ alkenyl”). In some embodiments, an alkenylgroup has 2 to 6 carbon atoms (“C₂₋₆ alkenyl”). In some embodiments, analkenyl group has 2 to 5 carbon atoms (“C₂₋₅ alkenyl”). In someembodiments, an alkenyl group has 2 to 4 carbon atoms (“C₂₋₄ alkenyl”).In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C₂₋₃alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C₂alkenyl”). The one or more carbon-carbon double bonds can be internal(such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples ofC₂₋₄ alkenyl groups include ethenyl (C₂), 1-propenyl (C₃), 2-propenyl(C₃), 1-butenyl (C₄), 2-butenyl (C₄), butadienyl (C₄), and the like.Examples of C₂₋₆ alkenyl groups include the aforementioned C₂₋₄ alkenylgroups as well as pentenyl (C₅), pentadienyl (C₅), hexenyl (C₆), and thelike. Additional examples of alkenyl include heptenyl (C₇), octenyl(C₈), octatrienyl (C₈), and the like. Unless otherwise specified, eachinstance of an alkenyl group is independently optionally substituted,i.e., unsubstituted (an “unsubstituted alkenyl”) or substituted (a“substituted alkenyl”) with one or more substituents. In certainembodiments, the alkenyl group is unsubstituted C₂₋₁₀ alkenyl. Incertain embodiments, the alkenyl group is substituted C₂₋₁₀ alkenyl. Inan alkenyl group, a C═C double bond for which the stereochemistry is notspecified (e.g., —CH═CHCH₃ or

may be an (E)- or (Z)-double bond.

“Alkynyl” refers to a radical of a straight-chain or branchedhydrocarbon group having from 2 to 20 carbon atoms, one or morecarbon-carbon triple bonds, and optionally one or more double bonds(“C₂₋₂₀ alkynyl”). In some embodiments, an alkynyl group has 2 to 10carbon atoms (“C₂₋₁₀ alkynyl”). In some embodiments, an alkynyl grouphas 2 to 9 carbon atoms (“C₂₋₉ alkynyl”). In some embodiments, analkynyl group has 2 to 8 carbon atoms (“C₂₋₈ alkynyl”). In someembodiments, an alkynyl group has 2 to 7 carbon atoms (“C₂₋₇ alkynyl”).In some embodiments, an alkynyl group has 2 to 6 carbon atoms (“C₂₋₆alkynyl”). In some embodiments, an alkynyl group has 2 to 5 carbon atoms(“C₂₋₅ alkynyl”). In some embodiments, an alkynyl group has 2 to 4carbon atoms (“C₂₋₄ alkynyl”). In some embodiments, an alkynyl group has2 to 3 carbon atoms (“C₂₋₃ alkynyl”). In some embodiments, an alkynylgroup has 2 carbon atoms (“C₂ alkynyl”). The one or more carbon-carbontriple bonds can be internal (such as in 2-butynyl) or terminal (such asin 1-butynyl). Examples of C₂₋₄ alkynyl groups include, withoutlimitation, ethynyl (C₂), 1-propynyl (C₃), 2-propynyl (C₃), 1-butynyl(C₄), 2-butynyl (C₄), and the like. Examples of C₂₋₆ alkenyl groupsinclude the aforementioned C₂₋₄ alkynyl groups as well as pentynyl (C₅),hexynyl (C₆), and the like. Additional examples of alkynyl includeheptynyl (C₇), octynyl (C₈), and the like. Unless otherwise specified,each instance of an alkynyl group is independently optionallysubstituted, i.e., unsubstituted (an “unsubstituted alkynyl”) orsubstituted (a “substituted alkynyl”) with one or more substituents. Incertain embodiments, the alkynyl group is unsubstituted C₂₋₁₀ alkynyl.In certain embodiments, the alkynyl group is substituted C₂₋₁₀ alkynyl.

“Carbocyclyl” or “carbocyclic” refers to a radical of a non-aromaticcyclic hydrocarbon group having from 3 to 10 ring carbon atoms (“C₃₋₁₀carbocyclyl”) and zero heteroatoms in the non-aromatic ring system. Insome embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms(“C₃₋₈ carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to6 ring carbon atoms (“C₃₋₆ carbocyclyl”). In some embodiments, acarbocyclyl group has 3 to 6 ring carbon atoms (“C₃₋₆ carbocyclyl”). Insome embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms(“C₅₋₁₀ carbocyclyl”). Exemplary C₃₋₆ carbocyclyl groups include,without limitation, cyclopropyl (C₃), cyclopropenyl (C₃), cyclobutyl(C₄), cyclobutenyl (C₄), cyclopentyl (C₅), cyclopentenyl (C₅),cyclohexyl (C₆), cyclohexenyl (C₆), cyclohexadienyl (C₆), and the like.Exemplary C₃₋₈ carbocyclyl groups include, without limitation, theaforementioned C₃₋₆ carbocyclyl groups as well as cycloheptyl (C₇),cycloheptenyl (C₇), cycloheptadienyl (C₇), cycloheptatrienyl (C₇),cyclooctyl (C₈), cyclooctenyl (C₈), bicyclo[2.2.1]heptanyl (C₇),bicyclo[2.2.2]octanyl (C₈), and the like. Exemplary C₃₋₁₀ carbocyclylgroups include, without limitation, the aforementioned C₃₋₈ carbocyclylgroups as well as cyclononyl (C₉), cyclononenyl (C₉), cyclodecyl (C₁₀),cyclodecenyl (C₁₀), octahydro-1H-indenyl (C₉), decahydronaphthalenyl(C₁₀), spiro[4.5]decanyl (C₁₀), and the like. As the foregoing examplesillustrate, in certain embodiments, the carbocyclyl group is eithermonocyclic (“monocyclic carbocyclyl”) or contain a fused, bridged orspiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) andcan be saturated or can be partially unsaturated. “Carbocyclyl” alsoincludes ring systems wherein the carbocyclic ring, as defined above, isfused with one or more aryl or heteroaryl groups wherein the point ofattachment is on the carbocyclic ring, and in such instances, the numberof carbons continue to designate the number of carbons in thecarbocyclic ring system. Unless otherwise specified, each instance of acarbocyclyl group is independently optionally substituted, i.e.,unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a“substituted carbocyclyl”) with one or more substituents. In certainembodiments, the carbocyclyl group is unsubstituted C₃₋₁₀ carbocyclyl.In certain embodiments, the carbocyclyl group is substituted C₃₋₁₀carbocyclyl.

In some embodiments, “carbocyclyl” is a monocyclic, saturatedcarbocyclyl group having from 3 to 10 ring carbon atoms (“C₃₋₁₀cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ringcarbon atoms (“C₃₋₈ cycloalkyl”). In some embodiments, a cycloalkylgroup has 3 to 6 ring carbon atoms (“C₃₋₆ cycloalkyl”). In someembodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C₅₋₆cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ringcarbon atoms (“C₅₋₁₀ cycloalkyl”). Examples of C₅₋₆ cycloalkyl groupsinclude cyclopentyl (C₅) and cyclohexyl (C₅). Examples of C₃₋₆cycloalkyl groups include the aforementioned C₅₋₆ cycloalkyl groups aswell as cyclopropyl (C₃) and cyclobutyl (C₄). Examples of C₃₋₈cycloalkyl groups include the aforementioned C₃₋₆ cycloalkyl groups aswell as cycloheptyl (C₇) and cyclooctyl (C₈). Unless otherwisespecified, each instance of a cycloalkyl group is independentlyunsubstituted (an “unsubstituted cycloalkyl”) or substituted (a“substituted cycloalkyl”) with one or more substituents. In certainembodiments, the cycloalkyl group is unsubstituted C₃₋₁₀ cycloalkyl. Incertain embodiments, the cycloalkyl group is substituted C₃₋₁₀cycloalkyl.

“Heterocyclyl” or “heterocyclic” refers to a radical of a 3- to10-membered non-aromatic ring system having ring carbon atoms and 1 to 4ring heteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“3-10 memberedheterocyclyl”). In heterocyclyl groups that contain one or more nitrogenatoms, the point of attachment can be a carbon or nitrogen atom, asvalency permits. A heterocyclyl group can either be monocyclic(“monocyclic heterocyclyl”) or a fused, bridged, or spiro ring system,such as a bicyclic system (“bicyclic heterocyclyl”), and can besaturated or can be partially unsaturated. Heterocyclyl bicyclic ringsystems can include one or more heteroatoms in one or both rings.“Heterocyclyl” also includes ring systems wherein the heterocyclic ring,as defined above, is fused with one or more carbocyclyl groups whereinthe point of attachment is either on the carbocyclyl or heterocyclicring, or ring systems wherein the heterocyclic ring, as defined above,is fused with one or more aryl or heteroaryl groups, wherein the pointof attachment is on the heterocyclic ring, and in such instances, thenumber of ring members continue to designate the number of ring membersin the heterocyclic ring system. Unless otherwise specified, eachinstance of heterocyclyl is independently optionally substituted, i.e.,unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a“substituted heterocyclyl”) with one or more substituents. In certainembodiments, the heterocyclyl group is unsubstituted 3-10 memberedheterocyclyl. In certain embodiments, the heterocyclyl group issubstituted 3-10 membered heterocyclyl.

In some embodiments, a heterocyclyl group is a 5-10 memberednon-aromatic ring system having ring carbon atoms and 1-4 ringheteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5-10 memberedheterocyclyl”). In some embodiments, a heterocyclyl group is a 5-8membered non-aromatic ring system having ring carbon atoms and 1-4 ringheteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, and sulfur (“5-8 membered heterocyclyl”). In someembodiments, a heterocyclyl group is a 5-6 membered non-aromatic ringsystem having ring carbon atoms and 1-4 ring heteroatoms, wherein eachheteroatom is independently selected from nitrogen, oxygen, and sulfur(“5-6 membered heterocyclyl”). In some embodiments, the 5-6 memberedheterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen,and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2ring heteroatoms selected from nitrogen, oxygen, and sulfur. In someembodiments, the 5-6 membered heterocyclyl has one ring heteroatomselected from nitrogen, oxygen, and sulfur.

Exemplary 3-membered heterocyclyl groups containing one heteroatominclude, without limitation, azirdinyl, oxiranyl, thiiranyl. Exemplary4-membered heterocyclyl groups containing one heteroatom include,without limitation, azetidinyl, oxetanyl and thietanyl. Exemplary5-membered heterocyclyl groups containing one heteroatom include,without limitation, tetrahydrofuranyl, dihydrofuranyl,tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl,and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groupscontaining two heteroatoms include, without limitation, dioxolanyl,oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-memberedheterocyclyl groups containing three heteroatoms include, withoutlimitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary6-membered heterocyclyl groups containing one heteroatom include,without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl,and thianyl. Exemplary 6-membered heterocyclyl groups containing twoheteroatoms include, without limitation, piperazinyl, morpholinyl,dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groupscontaining two heteroatoms include, without limitation, triazinanyl.Exemplary 7-membered heterocyclyl groups containing one heteroatominclude, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary8-membered heterocyclyl groups containing one heteroatom include,without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary5-membered heterocyclyl groups fused to a C₆ aryl ring (also referred toherein as a 5,6-bicyclic heterocyclic ring) include, without limitation,indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl,benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groupsfused to an aryl ring (also referred to herein as a 6,6-bicyclicheterocyclic ring) include, without limitation, tetrahydroquinolinyl,tetrahydroisoquinolinyl, and the like.

“Aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclicor tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pielectrons shared in a cyclic array) having 6-14 ring carbon atoms andzero heteroatoms provided in the aromatic ring system (“C₆₋₁₄ aryl”). Insome embodiments, an aryl group has six ring carbon atoms (“C₆ aryl”;e.g., phenyl). In some embodiments, an aryl group has ten ring carbonatoms (“C₁₀ aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). Insome embodiments, an aryl group has fourteen ring carbon atoms (“C₁₄aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein thearyl ring, as defined above, is fused with one or more carbocyclyl orheterocyclyl groups wherein the radical or point of attachment is on thearyl ring, and in such instances, the number of carbon atoms continue todesignate the number of carbon atoms in the aryl ring system. Unlessotherwise specified, each instance of an aryl group is independentlyoptionally substituted, i.e., unsubstituted (an “unsubstituted aryl”) orsubstituted (a “substituted aryl”) with one or more substituents. Incertain embodiments, the aryl group is unsubstituted C₆₋₁₄ aryl. Incertain embodiments, the aryl group is substituted C₆₋₁₄ aryl.

“Aralkyl” is a subset of alkyl and aryl and refers to an optionallysubstituted alkyl group substituted by an optionally substituted arylgroup. In certain embodiments, the aralkyl is optionally substitutedbenzyl. In certain embodiments, the aralkyl is benzyl. In certainembodiments, the aralkyl is optionally substituted phenethyl. In certainembodiments, the aralkyl is phenethyl.

“Heteroaryl” refers to a radical of a 5-10 membered monocyclic orbicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 pi electronsshared in a cyclic array) having ring carbon atoms and 1-4 ringheteroatoms provided in the aromatic ring system, wherein eachheteroatom is independently selected from nitrogen, oxygen and sulfur(“5-10 membered heteroaryl”). In heteroaryl groups that contain one ormore nitrogen atoms, the point of attachment can be a carbon or nitrogenatom, as valency permits. Heteroaryl bicyclic ring systems can includeone or more heteroatoms in one or both rings. “Heteroaryl” includes ringsystems wherein the heteroaryl ring, as defined above, is fused with oneor more carbocyclyl or heterocyclyl groups wherein the point ofattachment is on the heteroaryl ring, and in such instances, the numberof ring members continue to designate the number of ring members in theheteroaryl ring system. “Heteroaryl” also includes ring systems whereinthe heteroaryl ring, as defined above, is fused with one or more arylgroups wherein the point of attachment is either on the aryl orheteroaryl ring, and in such instances, the number of ring membersdesignates the number of ring members in the fused (aryl/heteroaryl)ring system. Bicyclic heteroaryl groups wherein one ring does notcontain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and thelike) the point of attachment can be on either ring, i.e., either thering bearing a heteroatom (e.g., 2-indolyl) or the ring that does notcontain a heteroatom (e.g., 5-indolyl).

In some embodiments, a heteroaryl group is a 5-10 membered aromatic ringsystem having ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In someembodiments, a heteroaryl group is a 5-8 membered aromatic ring systemhaving ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In someembodiments, a heteroaryl group is a 5-6 membered aromatic ring systemhaving ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In someembodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatomsselected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen,oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unlessotherwise specified, each instance of a heteroaryl group isindependently optionally substituted, i.e., unsubstituted (an“unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”)with one or more substituents. In certain embodiments, the heteroarylgroup is unsubstituted 5-14 membered heteroaryl. In certain embodiments,the heteroaryl group is substituted 5-14 membered heteroaryl.

Exemplary 5-membered heteroaryl groups containing one heteroatominclude, without limitation, pyrrolyl, furanyl, and thiophenyl.Exemplary 5-membered heteroaryl groups containing two heteroatomsinclude, without limitation, imidazolyl, pyrazolyl, oxazolyl,isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroarylgroups containing three heteroatoms include, without limitation,triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-memberedheteroaryl groups containing four heteroatoms include, withoutlimitation, tetrazolyl. Exemplary 6-membered heteroaryl groupscontaining one heteroatom include, without limitation, pyridinyl.Exemplary 6-membered heteroaryl groups containing two heteroatomsinclude, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl.Exemplary 6-membered heteroaryl groups containing three or fourheteroatoms include, without limitation, triazinyl and tetrazinyl,respectively. Exemplary 7-membered heteroaryl groups containing oneheteroatom include, without limitation, azepinyl, oxepinyl, andthiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, withoutlimitation, indolyl, isoindolyl, indazolyl, benzotriazolyl,benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl,benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl,benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, andpurinyl. Exemplary 6,6-bicyclic heteroaryl groups include, withoutlimitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl,cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

“Heteroaralkyl” is a subset of alkyl and heteroaryl and refers to anoptionally substituted alkyl group substituted by an optionallysubstituted heteroaryl group.

“Unsaturated” or “partially unsaturated” refers to a group that includesat least one double or triple bond. A “partially unsaturated” ringsystem is further intended to encompass rings having multiple sites ofunsaturation, but is not intended to include aromatic groups (e.g., arylor heteroaryl groups). Likewise, “saturated” refers to a group that doesnot contain a double or triple bond, i.e., contains all single bonds.

Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroarylgroups, which are divalent bridging groups, are further referred tousing the suffix -ene, e.g., alkylene, alkenylene, alkynylene,carbocyclylene, heterocyclylene, arylene, and heteroarylene.

An atom, moiety, or group described herein may be unsubstituted orsubstituted, as valency permits, unless otherwise provided expressly.The term “optionally substituted” refers to substituted orunsubstituted.

A group is optionally substituted unless expressly provided otherwise.The term “optionally substituted” refers to being substituted orunsubstituted. In certain embodiments, alkyl, alkenyl, alkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl groups are optionallysubstituted (e.g., “substituted” or “unsubstituted” alkyl, “substituted”or “unsubstituted” alkenyl, “substituted” or “unsubstituted” alkynyl,“substituted” or “unsubstituted” carbocyclyl, “substituted” or“unsubstituted” heterocyclyl, “substituted” or “unsubstituted” aryl or“substituted” or “unsubstituted” heteroaryl group). In general, the term“substituted”, whether preceded by the term “optionally” or not, meansthat at least one hydrogen present on a group (e.g., a carbon ornitrogen atom) is replaced with a permissible substituent, e.g., asubstituent which upon substitution results in a stable compound, e.g.,a compound which does not spontaneously undergo transformation such asby rearrangement, cyclization, elimination, or other reaction. Unlessotherwise indicated, a “substituted” group has a substituent at one ormore substitutable positions of the group, and when more than oneposition in any given structure is substituted, the substituent iseither the same or different at each position. The term “substituted” iscontemplated to include substitution with all permissible substituentsof organic compounds, any of the substituents described herein thatresults in the formation of a stable compound. The present disclosurecontemplates any and all such combinations in order to arrive at astable compound. For purposes of this disclosure, heteroatoms such asnitrogen may have hydrogen substituents and/or any suitable substituentas described herein which satisfy the valencies of the heteroatoms andresults in the formation of a stable moiety. In certain embodiments, thesubstituent is a carbon atom substituent. In certain embodiments, thesubstituent is a nitrogen atom substituent. In certain embodiments, thesubstituent is an oxygen atom substituent. In certain embodiments, thesubstituent is a sulfur atom substituent.

Exemplary carbon atom substituents include, but are not limited to,halogen, —CN, —NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OR^(aa), —ON(R^(bb))₂,—N(R^(bb))₂, —N(R^(bb))₃ ^(|)X⁻, —N(OR^(cc))R^(bb), —SH, —SR^(aa),—SSR^(cc), —C(═O)R^(aa), —CO₂H, —CHO, —C(OR^(cc))₂, —CO₂R^(aa),—OC(═O)R^(aa), —OCO₂R^(aa), —C(═O)N(R^(bb))₂, —OC(═O)N(R^(bb))₂,—NR^(bb)C(═O)R^(aa), —NR^(bb)CO₂R^(aa), —NR^(bb)C(═O)N(R^(bb))₂,—C(═NR^(bb))R^(aa), —C(═NR^(bb))OR^(aa), —OC(═NR^(bb))R^(aa),—OC(═NR^(bb))OR^(aa), —C(═NR^(bb))N(R^(bb))₂, —OC(═NR^(bb))N(R^(bb))₂,—NR^(bb)C(═NR^(bb))N(R^(bb))₂, —C(═O)NR^(bb)SO₂R^(aa),—NR^(bb)SO₂R^(aa), —SO₂N(R^(bb))₂, —SO₂R^(aa), —SO₂OR^(aa), —OSO₂R^(aa),—S(═O)R^(aa), —OS(═O)R^(aa), —Si(R^(aa))₃, —OSi(R^(aa))₃—C(═S)N(R^(bb))₂, —C(═O)SR^(aa), —C(═S)SR^(aa), —SC(═S)SR^(aa),—SC(═O)SR^(aa), —OC(═O)SR^(aa), —SC(═O)OR^(aa), —SC(═O)R^(aa),—P(═O)(R^(aa))₂, —P(═O)(OR^(cc))₂, —OP(═O)(R^(aa))₂, —OP(═O)(OR^(cc))₂,—P(═O)(N(R^(bb))₂)₂, —OP(═O)(N(R^(bb))₂)₂, —NR^(bb)P(═O)(R^(aa))₂,—NR^(bb)P(═O)(OR^(cc))₂, —NR^(bb)P(═O)(N(R^(bb))₂)₂, —P(R^(cc))₂,—P(OR^(cc))₂, —P(R^(cc))₃ ⁺X⁻, —P(OR^(cc))₃ ⁺X⁻, —P(R^(cc))₄,—P(OR^(cc))₄, —OP(R^(cc))₂, —OP(R^(cc))₃ ⁺X⁻, —OP(OR^(cc))₂,—OP(OR^(cc))₃ ⁺X⁻, —OP(R^(cc))₄, —OP(OR^(cc))₄, —B(R^(aa))₂,—B(OR^(cc))₂, —BR^(aa)(OR^(cc)), C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocyclyl, 3-14 membered heterocyclyl,C₆₋₁₄ aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl,alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl isindependently substituted with 0,1,2,3,4, or 5 R^(dd) groups; wherein X⁻is a counterion;

or two geminal hydrogens on a carbon atom are replaced with the group═O, ═S, ═NN(R^(bb))₂, ═NNR^(bb)C(═O)R^(aa), ═NNR^(bb)C(═O)OR^(aa),═NNR^(bb)S(═O)₂R^(aa), ═NR^(bb), or ═NOR^(cc);

each instance of R^(aa) is, independently, selected from C₁₋₁₀ alkyl,C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocyclyl,3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 membered heteroaryl, ortwo R^(aa) groups are joined to form a 3-14 membered heterocyclyl or5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is independentlysubstituted with 0,1,2,3,4, or 5 R^(dd) groups;

each instance of R^(bb) is, independently, selected from hydrogen, —OH,—OR^(aa), —N(R^(cc))₂, —CN, —C(═O)R^(aa), —C(═O)N(R^(cc))₂, —CO₂R^(aa),—SO₂R^(aa), —C(═NR^(cc))OR^(aa), —C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂,—SO₂R^(cc), —SO₂OR^(cc), —SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc),—C(═S)SR^(cc), —P(═O)(R^(aa))₂, —P(═O)(OR^(cc))₂, —P(═O)(N(R^(cc))₂)₂,C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 memberedheteroaryl, or two R^(bb) groups are joined to form a 3-14 memberedheterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl,alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl isindependently substituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups;wherein X⁻ is a counterion;

each instance of R^(cc) is, independently, selected from hydrogen, C₁₋₁₀alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 memberedheteroaryl, or two R^(cc) groups are joined to form a 3-14 memberedheterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl,alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl isindependently substituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups;

each instance of R^(dd) is, independently, selected from halogen, —CN,—NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OR^(ee), —ON(R^(ff))₂, —N(R^(ff))₂,—N(R^(ff))₃ ⁺X⁻, —N(OR^(ee))R^(ff), —SH, —SR^(ee), —SSR^(ee),—C(═O)R^(ee), —CO₂H, —CO₂R^(ee), —OC(═O)R^(ee), —OCO₂R^(ee),—C(═O)N(R^(ff))₂, —OC(═O)N(R^(ff))₂, —NR^(ff)C(═O)R^(ee),—NR^(ff)CO₂R^(ee), —NR^(ff)C(═O)N(R^(ff))₂, —C(═NR^(ff))OR^(ee),—OC(═NR^(ff))R^(ee), —OC(═NR^(ff))OR^(ee), —C(═NR^(ff))N(R^(ff))₂,—OC(═NR^(ff))N(R^(ff))₂, —NR^(ff)C(═NR^(ff))N(R^(ff))₂,—NR^(ff)SO₂R^(ee), —SO₂N(R^(ff))₂, —SO₂R^(ee), —SO₂OR^(ee), —OSO₂R^(ee),—S(═O)R^(ee), —Si(R^(ee))₃, —OSi(R^(ee))₃, —C(═S)N(R^(ff))₂,—C(═O)SR^(ee), —C(═S)SR^(ee), —SC(═S)SR^(ee), —P(═O)(OR^(ee))₂,—P(═O)(R^(ee))₂, —OP(═O)(R^(ee))₂, —OP(═O)(OR^(ee))₂, C₁₋₆ alkyl, C₁₋₆perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl, 3-10membered heterocyclyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, whereineach alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^(gg)groups, or two geminal R^(dd) substituents can be joined to form ═O or═S; wherein X⁻ is a counterion;

each instance of R^(ee) is, independently, selected from C₁₋₆ alkyl,C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl, C₆₋₁₀aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, whereineach alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^(gg)groups;

each instance of R^(ff) is, independently, selected from hydrogen, C₁₋₆alkyl, C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl,3-10 membered heterocyclyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl, ortwo R^(ff) groups are joined to form a 3-14 membered heterocyclyl or5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is independentlysubstituted with 0, 1, 2, 3, 4, or 5 R^(gg) groups; and

each instance of R^(gg) is, independently, halogen, —CN, —NO₂, —N₃,—SO₂H, —SO₃H, —OH, —OC₁₋₆ alkyl, —ON(C₁₋₆ alkyl)₂, —N(C₁₋₆ alkyl)₂,—N(C₁₋₆ alkyl)₃ ⁺X⁻, —NH(C₁₋₆ alkyl)₂ ⁺X⁻, —NH₂(C₁₋₆ alkyl)⁺X⁻, —NH₃⁺X⁻, —N(OC₁₋₆ alkyl)(C₁₋₆ alkyl), —N(OH)(C₁₋₆ alkyl), —NH(OH), —SH,—SC₁₋₆ alkyl, —SS(C₁₋₆ alkyl), —C(═O)(C₁₋₆ alkyl), —CO₂H, —CO₂(C₁₋₆alkyl), —OC(═O)(C₁₋₆ alkyl), —OCO₂(C₁₋₆ alkyl), —C(═O)NH₂, —C(═O)N(C₁₋₆alkyl)₂, —OC(═O)NH(C₁₋₆ alkyl), —NHC(═O)(C₁₋₆ alkyl), —N(C₁₋₆alkyl)C(═O)(C₁₋₆ alkyl), —NHCO₂(C₁₋₆ alkyl), —NHC(═O)N(C₁₋₆ alkyl)₂,—NHC(═O)NH(C₁₋₆ alkyl), —NHC(═O)NH₂, —C(═NH)O(C₁₋₆ alkyl), —OC(═NH)(C₁₋₆alkyl), —OC(═NH)OC₁₋₆ alkyl, —C(═NH)N(C₁₋₆ alkyl)₂, —C(═NH)NH(C₁₋₆alkyl), —C(═NH)NH₂, —OC(═NH)N(C₁₋₆ alkyl)₂, —OC(NH)NH(C₁₋₆ alkyl),—OC(NH)NH₂, —NHC(NH)N(C₁₋₆ alkyl)₂, —NHC(═NH)NH₂, —NHSO₂(C₁₋₆ alkyl),—SO₂N(C₁₋₆ alkyl)₂, —SO₂NH(C₁₋₆ alkyl), —SO₂NH₂, —SO₂C₁₋₆ alkyl,—SO₂OC₁₋₆ alkyl, —OSO₂C₁₋₆ alkyl, —SOC₁₋₆ alkyl, —Si(C₁₋₆ alkyl)₃,—OSi(C₁₋₆ alkyl)₃ —C(═S)N(C₁₋₆ alkyl)₂, C(═S)NH(C₁₋₆ alkyl), C(═S)NH₂,—C(═O)S(C₁₋₆ alkyl), —C(═S)SC₁₋₆ alkyl, —SC(═S)SC₁₋₆ alkyl, —P(═O)(OC₁₋₆alkyl)₂, —P(═O)(C₁₋₆ alkyl)₂, —OP(═O)(C₁₋₆ alkyl)₂, —OP(═O)(OC₁₋₆alkyl)₂, C₁₋₆ alkyl, C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₁₀ carbocyclyl, C₆₋₁₀ aryl, 3-10 membered heterocyclyl, 5-10 memberedheteroaryl; or two geminal R^(gg) substituents can be joined to form ═Oor ═S; wherein X⁻ is a counterion.

each instance of R^(gg) is, independently, halogen, —CN, —NO₂, —N₃,—SO₂H, —SO₃H, —OH, —OC₁₋₆ alkyl, —ON(C₁₋₆ alkyl)₂, —N(C₁₋₆ alkyl)₂,—N(C₁₋₆ alkyl)₃ ⁺X⁻, —NH(C₁₋₆ alkyl)₂ ⁺X⁻, —NH₂(C₁₋₆ alkyl)⁺X⁻, —NH₃⁺X⁻, —N(OC₁₋₆ alkyl)(C₁₋₆ alkyl), —N(OH)(C₁₋₆ alkyl), —NH(OH), —SH,—SC₁₋₆ alkyl, —SS(C₁₋₆ alkyl), —C(═O)(C₁₋₆ alkyl), —CO₂H, —CO₂(C₁₋₆alkyl), —OC(═O)(C₁₋₆ alkyl), —OCO₂(C₁₋₆ alkyl), —C(═O)NH₂, —C(═O)N(C₁₋₆alkyl)₂, —OC(═O)NH(C₁ ₆ alkyl), —NHC(═O)(C₁ ₆ alkyl), —N(C₁ ₆alkyl)C(═O)(C₁ ₆ alkyl), —NHCO₂(C₁₋₆ alkyl), —NHC(═O)N(C₁₋₆ alkyl)₂,—NHC(═O)NH(C₁₋₆ alkyl), —NHC(═O)NH₂, —C(═NH)O(C₁₋₆ alkyl), —OC(═NH)(C₁₋₆alkyl), —OC(═NH)OC₁₋₆ alkyl, —C(═NH)N(C₁₋₆ alkyl)₂, —C(═NH)NH(C₁₋₆alkyl), —C(═NH)NH₂, —OC(═NH)N(C₁₋₆ alkyl)₂, —OC(NH)NH(C₁₋₆ alkyl),—OC(NH)NH₂, —NHC(NH)N(C₁₋₆ alkyl)₂, —NHC(═NH)NH₂, —NHSO₂(C₁₋₆ alkyl),—SO₂N(C₁₋₆ alkyl)₂, —SO₂NH(C₁₋₆ alkyl), —SO₂NH₂, —SO₂C₁₋₆ alkyl,—SO₂OC₁₋₆ alkyl, —OSO₂C₁₋₆ alkyl, —SOC₁₋₆ alkyl, —Si(C₁₋₆ alkyl)₃,—OSi(C₁₋₆ alkyl)₃ —C(═S)N(C₁₋₆ alkyl)₂, C(═S)NH(C₁₋₆ alkyl), C(═S)NH₂,—C(═O)S(C₁₋₆ alkyl), —C(═S)SC₁₋₆ alkyl, —SC(═S)SC₁₋₆ alkyl, —P(═O)(OC₁₋₆alkyl)₂, —P(═O)(C₁₋₆ alkyl)₂, —OP(═O)(C₁₋₆ alkyl)₂, —OP(═O)(OC₁₋₆alkyl)₂, C₁₋₆ alkyl, C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₁₀ carbocyclyl, C₆₋₁₀ aryl, 3-10 membered heterocyclyl, 5-10 memberedheteroaryl; or two geminal R^(gg) substituents can be joined to form ═Oor ═S; wherein X⁻ is a counterion.

A “counterion” or “anionic counterion” is a negatively charged groupassociated with a positively charged group in order to maintainelectronic neutrality. An anionic counterion may be monovalent (i.e.,including one formal negative charge). An anionic counterion may also bemultivalent (i.e., including more than one formal negative charge), suchas divalent or trivalent. Exemplary counterions include halide ions(e.g., F, Cl, Br, I), NO₃, ClO₄, OH, H₂PO₄ ⁻, HSO₄ ⁻, sulfonate ions(e.g., methansulfonate, trifluoromethanesulfonate, p-toluenesulfonate,benzenesulfonate, 10-camphor sulfonate, naphthalene-2-sulfonate,naphthalene-1-sulfonic acid-5-sulfonate, ethan-1-sulfonicacid-2-sulfonate, and the like), carboxylate ions (e.g., acetate,propanoate, benzoate, glycerate, lactate, tartrate, glycolate,gluconate, and the like), BF₄ ⁻, PF₄ ⁻, PF₆ ⁻, AsF₆ ⁻, SbF₆ ⁻,B[3,5-(CF₃)₂C₆H₃]₄]⁻, BPh₄ ⁻, Al(OC(CF₃)₃)₄ ⁻, and a carborane anion(e.g., CB₁₁H₁₂ ⁻ or (HCB₁₁Me₅Br₆)⁻). Exemplary counterions which may bemultivalent include CO₃ ²⁻, HPO₄ ²⁻, PO₄ ³⁻, B₄O₇ ²⁻, SO₄ ²⁻, S₂O₃ ²⁻,carboxylate anions (e.g., tartrate, citrate, fumarate, maleate, malate,malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate,azelate, sebacate, salicylate, phthalates, aspartate, glutamate, and thelike), and carboranes.

“Halo” or “halogen” refers to fluorine (fluoro, —F), chlorine (chloro,—Cl), bromine (bromo, —Br), or iodine (iodo, —I).

“Acyl” refers to a moiety selected from the group consisting of—C(═O)R^(aa), —CHO, —CO₂R^(aa), —C(═O)N(R^(bb))₂, —C(═NR^(bb))R^(aa),—C(═NR^(bb))OR^(aa), —C(═NR^(bb))N(R^(bb))₂, —C(═O)NR^(bb)SO₂R^(aa),—C(═S)N(R^(bb))₂, —C(═O)SR^(aa), or —C(═S)SR^(aa), wherein R^(aa) andR^(bb) are as defined herein.

Nitrogen atoms can be substituted or unsubstituted as valency permits,and include primary, secondary, tertiary, and quaternary nitrogen atoms.Exemplary nitrogen atom substituents include, but are not limited to,hydrogen, —OH, —OR^(aa), —N(R^(cc))₂, —CN, —C(═O)R^(aa),—C(═O)N(R^(cc))₂, —CO₂R^(aa), —SO₂R^(aa), —C(═NR^(bb))R^(aa),—C(═NR^(cc))OR^(aa), —C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂, —SO₂R^(cc),—SO₂OR^(cc), —SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc), —C(═S)SR^(cc),—P(═O)(OR^(cc))₂, —P(═O)(R^(aa))₂, —P(═O)(N(R^(cc))₂)₂, C₁₋₁₀ alkyl,C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocyclyl,3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 membered heteroaryl, ortwo R^(cc) groups attached to a nitrogen atom are joined to form a 3-14membered heterocyclyl or 5-14 membered heteroaryl ring, wherein eachalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroarylis independently substituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups, andwherein R^(aa), R^(bb), R^(cc), and R^(dd) are as defined above.

In certain embodiments, the substituent present on a nitrogen atom is anitrogen protecting group (also referred to as an amino protectinggroup). Nitrogen protecting groups include, but are not limited to, —OH,—OR^(aa), —N(R^(cc))₂, —C(═O)R^(aa), —C(═O)N(R^(cc))₂, —CO₂R^(aa),—SO₂R^(aa), —C(═NR^(cc))R^(aa), —C(═NR^(cc))OR^(aa),—C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂, —SO₂R^(cc), —SO₂OR^(cc),—SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc), —C(═S)SR^(cc), C₁₋₁₀ alkyl(e.g., aralkyl, heteroaralkyl), C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 memberedheteroaryl groups, wherein each alkyl, alkenyl, alkynyl, carbocyclyl,heterocyclyl, aralkyl, aryl, and heteroaryl is independently substitutedwith 0, 1, 2, 3, 4, or 5 R^(dd) groups, and wherein R^(aa), R^(bb),R^(cc) and R^(dd) are as defined herein. Nitrogen protecting groups arewell known in the art and include those described in detail inProtecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts,3^(rd) edition, John Wiley & Sons, 1999, incorporated by referenceherein.

For example, nitrogen protecting groups such as amide groups (e.g.,—C(═O)R^(aa)) include, but are not limited to, formamide, acetamide,chloroacetamide, trichloroacetamide, trifluoroacetamide,phenylacetamide, 3-phenylpropanamide, picolinamide,3-pyridylcarboxamide, N-benzoylphenylalanyl derivative, benzamide,p-phenylbenzamide, o-nitophenylacetamide, o-nitrophenoxyacetamide,acetoacetamide, (N′-dithiobenzyloxyacylamino)acetamide,3-(p-hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide,2-methyl-2-(o-nitrophenoxy)propanamide,2-methyl-2-(o-phenylazophenoxy)propanamide, 4-chlorobutanamide,3-methyl-3-nitrobutanamide, o-nitrocinnamide, N-acetylmethioninederivative, o nitrobenzamide, and o (benzoyloxymethyl)benzamide.

Nitrogen protecting groups such as carbamate groups (e.g.,—C(═O)OR^(aa)) include, but are not limited to, methyl carbamate,ethylcarbamate, 9-fluorenylmethyl carbamate (Fmoc),9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluoroenylmethylcarbamate,2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methylcarbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc),2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate(Teoc), 2-phenylethyl carbamate (hZ), 1-(1-adamantyl)-1-methylethylcarbamate (Adpoc), 1,1-dimethyl-2-haloethyl carbamate,1,1-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC),1,1-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC),1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc),1-(3,5-di-t-butylphenyl)-1-methylethyl carbamate (t-Bumeoc), 2-(2′- and4′-pyridyl)ethyl carbamate (Pyoc), 2-(N,N-dicyclohexylcarboxamido)ethylcarbamate, t-butyl carbamate (BOC or Boc), 1-adamantyl carbamate (Adoc),vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropylallylcarbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate(Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyldithiocarbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz),p-nitobenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzylcarbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzylcarbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate,2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate,2-(p-toluenesulfonyl)ethyl carbamate, [2-(1,3-dithianyl)]methylcarbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc),2,4-dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethyl carbamate(Peoc), 2-triphenylphosphonioisopropyl carbamate (Ppoc),1,1-dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate,p-(dihydroxyboryl)benzyl carbamate, 5-benzisoxazolylmethyl carbamate,2-(trifluoromethyl)-6-chromonylmethyl carbamate (Tcroc), m-nitrophenylcarbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate,3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl(o-nitrophenyl)methylcarbamate, t-amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzylcarbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentylcarbamate, cyclopropylmethyl carbamate, p-decyloxybenzyl carbamate,2,2-dimethoxyacylvinyl carbamate, o-(N,N-dimethylcarboxamido)benzylcarbamate, 1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl carbamate,1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate,2-furanylmethyl carbamate, 2-iodoethyl carbamate, isoborynl carbamate,isobutyl carbamate, isonicotinyl carbamate,p-(p′-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl carbamate,1-methylcyclohexyl carbamate, 1-methyl-1-cyclopropylmethyl carbamate,1-methyl-1-(3,5-dimethoxyphenyl)ethyl carbamate,1-methyl-1-(p-phenylazophenyl)ethyl carbamate, 1-methyl-1-phenylethylcarbamate, 1-methyl-1-(4-pyridyl)ethyl carbamate, phenyl carbamate,p-(phenylazo)benzyl carbamate, 2,4,6-tri-t-butylphenyl carbamate,4-(trimethylammonium)benzyl carbamate, and 2,4,6-trimethylbenzylcarbamate.

Nitrogen protecting groups such as sulfonamide groups (e.g.,—S(═O)₂R^(aa)) include, but are not limited to, p-toluenesulfonamide(Ts), benzenesulfonamide, 2,3,6,-trimethyl-4-methoxybenzenesulfonamide(Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb),2,6-dimethyl-4-methoxybenzenesulfonamide (Pme),2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte),4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide(Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds),2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide(Ms), β-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide,4-(4′,8′-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS),benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.

Other nitrogen protecting groups include, but are not limited to,phenothiazinyl-(10)-acyl derivative, N′-p-toluenesulfonylaminoacylderivative, N′-phenylaminothioacyl derivative, N-benzoylphenylalanylderivative, N-acetylmethionine derivative,4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts),N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole,N-1,1,4,4-tetramethyldisilylazacyclopentane adduct (STABASE),5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, 1-substituted3,5-dinitro-4-pyridone, N-methylamine, N-allylamine,N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine,N-(1-isopropyl-4-nitro-2-oxo-3-pyroolin-3-yl)amine, quaternary ammoniumsalts, N-benzylamine, N-di(4-methoxyphenyl)methylamine,N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr),N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr),N-9-phenylfluorenylamine (PhF),N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm),N-2-picolylamino N′-oxide, N-1,1-dimethylthiomethyleneamine,N-benzylideneamine, N-p-methoxybenzylideneamine,N-diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine,N-(N′,N′-dimethylaminomethylene)amine, N,N′-isopropylidenediamine,N-p-nitrobenzylideneamine, N-salicylideneamine,N-5-chlorosalicylideneamine,N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine,N-cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)amine,N-borane derivative, N-diphenylborinic acid derivative,N-[phenyl(pentaacylchromium- or tungsten)acyl]amine, N-copper chelate,N-zinc chelate, N-nitroamine, N-nitrosoamine, amine N-oxide,diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt),diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzylphosphoramidate, diphenyl phosphoramidate, benzenesulfenamide,o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide,pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide,triphenylmethylsulfenamide, and 3-nitropyridinesulfenamide (Npys).

Exemplary oxygen atom substituents include, but are not limited to,—R^(aa), —C(═O)SR^(aa), —C(═O)R^(aa), —CO₂R^(aa), —C(═O)N(R^(bb))₂,—C(═NR^(bb))R^(aa), —C(═NR^(bb))OR^(aa), —C(═NR^(bb))N(R^(bb))₂,—S(═O)R^(aa), —SO₂R^(aa), —Si(R^(aa))₃, —P(R^(cc))₂, —P(R^(cc))₃ ⁺X⁻,—P(OR^(cc))₂, —P(OR^(cc))₃ ⁺X⁻, —P(═O)(R^(aa))₂, —P(═O)(OR^(cc))₂, and—P(═O)(N(R^(bb))₂)₂, wherein X⁻, R^(aa), R^(bb), and R^(cc) are asdefined herein. In certain embodiments, the oxygen atom substituentpresent on an oxygen atom is an oxygen protecting group (also referredto as a hydroxyl protecting group). Oxygen protecting groups are wellknown in the art and include those described in detail in ProtectingGroups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3^(rd)edition, John Wiley & Sons, 1999, incorporated herein by reference.Exemplary oxygen protecting groups include, but are not limited to,methyl, t-butyloxycarbonyl (BOC or Boc), methoxylmethyl (MOM),methylthiomethyl (MTM), t-butylthiomethyl,(phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM),p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM),guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM),siloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl,bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR),tetrahydropyranyl (THP), 3-bromotetrahydropyranyl,tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl(MTHP), 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranylS,S-dioxide,1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl(CTMP),1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl,2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl,1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl,1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl,2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl,t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl,benzyl (Bn), p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl,p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl,p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxido,diphenylmethyl, p,p′-dinitrobenzhydryl, 5-dibenzosuberyl,triphenylmethyl, α-naphthyldiphenylmethyl,p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl,tri(p-methoxyphenyl)methyl, 4-(4′-bromophenacyloxyphenyl)diphenylmethyl,4,4′,4″-tris(4,5-dichlorophthalimidophenyl)methyl,4,4′,4″-tris(levulinoyloxyphenyl)methyl,4,4′,4″-tris(benzoyloxyphenyl)methyl,3-(imidazol-1-yl)bis(4′,4″-dimethoxyphenyl)methyl,1,1-bis(4-methoxyphenyl)-1′-pyrenylmethyl, 9-anthryl,9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl,1,3-benzodisulfuran-2-yl, benzisothiazolyl S,S-dioxido, trimethylsilyl(TMS), triethylsilyl (TES), triisopropylsilyl (TIPS),dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS),dimethylthexylsilyl, t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl(TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl,diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formate,benzoylformate, acetate, chloroacetate, dichloroacetate,trichloroacetate, trifluoroacetate, methoxyacetate,triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate,3-phenylpropionate, 4-oxopentanoate (levulinate),4,4-(ethylenedithio)pentanoate (levulinoyldithioacetal), pivaloate,adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate,2,4,6-trimethylbenzoate (mesitoate), alkyl methyl carbonate,9-fluorenylmethyl carbonate (Fmoc), alkyl ethyl carbonate, alkyl2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate(TMSEC), 2-(phenylsulfonyl) ethyl carbonate (Psec),2-(triphenylphosphonio) ethyl carbonate (Peoc), alkyl isobutylcarbonate, alkyl vinyl carbonate alkyl allyl carbonate, alkylp-nitrophenyl carbonate, alkyl benzyl carbonate, alkyl p-methoxybenzylcarbonate, alkyl 3,4-dimethoxybenzyl carbonate, alkyl o-nitrobenzylcarbonate, alkyl p-nitrobenzyl carbonate, alkyl S-benzyl thiocarbonate,4-ethoxy-1-napththyl carbonate, methyl dithiocarbonate, 2-iodobenzoate,4-azidobutyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate,2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl,4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate,2,6-dichloro-4-methylphenoxyacetate,2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate,2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate,isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate,o-(methoxyacyl)benzoate, α-naphthoate, nitrate, alkylN,N,N′,N′-tetramethylphosphorodiamidate, alkyl N-phenylcarbamate,borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate,sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate(Ts).

A “hydrocarbon chain” refers to a substituted or unsubstituted divalentalkyl, alkenyl, or alkynyl group. A hydrocarbon chain includes (1) oneor more chains of carbon atoms immediately between the two radicals ofthe hydrocarbon chain; (2) optionally one or more hydrogen atoms on thechain(s) of carbon atoms; and (3) optionally one or more substituents(“non-chain substituents,” which are not hydrogen) on the chain(s) ofcarbon atoms. A chain of carbon atoms consists of consecutivelyconnected carbon atoms (“chain atoms” or “carbon units”) and does notinclude hydrogen atoms or heteroatoms. However, a non-chain substituentof a hydrocarbon chain may include any atoms, including hydrogen atoms,carbon atoms, and heteroatoms. For example, hydrocarbon chain—C^(A)H(C^(B)H₂C^(C)H₃)— includes one chain atom C^(A), one hydrogenatom on C^(A), and non-chain substituent —(C^(B)H₂C^(C)H₃). The term“C_(x) hydrocarbon chain,” wherein x is a positive integer, refers to ahydrocarbon chain that includes x number of chain atom(s) between thetwo radicals of the hydrocarbon chain. If there is more than onepossible value of x, the smallest possible value of x is used for thedefinition of the hydrocarbon chain. For example, —CH(C₂H₅)— is a C₁hydrocarbon chain, and

is a C₃ hydrocarbon chain. When a range of values is used, the meaningof the range is as described herein. For example, a C₃₋₁₀ hydrocarbonchain refers to a hydrocarbon chain where the number of chain atoms ofthe shortest chain of carbon atoms immediately between the two radicalsof the hydrocarbon chain is 3, 4, 5, 6, 7, 8, 9, or 10. A hydrocarbonchain may be saturated (e.g., —(CH₂)₄—). A hydrocarbon chain may also beunsaturated and include one or more C═C and/or C≡C bonds anywhere in thehydrocarbon chain. For instance, —CH═CH—(CH₂)₂—, —CH₂—C≡C—CH₂—, and—C≡C—CH═CH— are all examples of an unsubstituted and unsaturatedhydrocarbon chain. In certain embodiments, the hydrocarbon chain isunsubstituted (e.g., —C≡C— or —(CH₂)₄—). In certain embodiments, thehydrocarbon chain is substituted (e.g., —CH(C₂H₅)— and —CF₂—). Any twosubstituents on the hydrocarbon chain may be joined to form anoptionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl, or optionally substituted heteroaryl ring.For instance,

are all examples of a hydrocarbon chain. In contrast, in certainembodiments,

are not within the scope of the hydrocarbon chains described herein.When a chain atom of a C_(x) hydrocarbon chain is replaced with aheteroatom, the resulting group is referred to as a C_(x) hydrocarbonchain wherein a chain atom is replaced with a heteroatom, as opposed toa C_(x-1) hydrocarbon chain. For example,

is a C₃ hydrocarbon chain wherein one chain atom is replaced with anoxygen atom.

The term “leaving group” is given its ordinary meaning in the art ofsynthetic organic chemistry and refers to an atom or a group capable ofbeing displaced by a nucleophile. See, for example, Smith, MarchAdvanced Organic Chemistry 6th ed. (501-502). Examples of suitableleaving groups include, but are not limited to, halogen (such as F, Cl,Br, or I (iodine)), alkoxycarbonyloxy, aryloxycarbonyloxy,alkanesulfonyloxy, arenesulfonyloxy, alkyl-carbonyloxy (e.g., acetoxy),arylcarbonyloxy, aryloxy, methoxy, N,O-dimethylhydroxylamino, pixyl, andhaloformates. In some cases, the leaving group is an activatedsubstituted hydroxyl group (e.g., —OC(═O)SR^(aa), —OC(═O)R^(aa),—OCO₂R^(aa), —OC(═O)N(R^(bb))₂, —OC(═NR^(bb))R^(aa),—OC(═NR^(bb))OR^(aa), —OC(═NR^(bb))N(R^(bb))₂, —OS(═O)R^(aa),—OSO₂R^(aa), —OP(R^(cc))₂, —OP(R^(cc))₃, —OP(═O)₂R^(aa),—OP(═O)(R^(aa))₂, —OP(═O)(OR^(cc))₂, —OP(═O)₂N(R^(bb))₂, and—OP(═O)(NR^(bb))₂, wherein R^(aa), R^(bb), and R^(cc) are as definedherein). In some cases, the leaving group is a sulfonic acid ester, suchas toluenesulfonate (tosylate, —OTs), methanesulfonate (mesylate, —OMs),p-bromobenzenesulfonyloxy (brosylate, —OBs), —OS(═O)₂(CF₂)₃CF₃(nonaflate, —ONf), or trifluoromethanesulfonate (triflate, —OTf). Insome cases, the leaving group is a brosylate, such asp-bromobenzenesulfonyloxy. In some cases, the leaving group is anosylate, such as 2-nitrobenzenesulfonyloxy. In some embodiments, theleaving group is a sulfonate-containing group. In some embodiments, theleaving group is a tosylate group. The leaving group may also be aphosphineoxide (e.g., formed during a Mitsunobu reaction) or an internalleaving group such as an epoxide or cyclic sulfate. Other non-limitingexamples of leaving groups are water, ammonia, alcohols, ether moieties,thioether moieties, zinc halides, magnesium moieties, diazonium salts,and copper moieties.

The term “pharmaceutically acceptable salt” refers to those salts whichare, within the scope of sound medical judgment, suitable for use incontact with the tissues of humans and lower animals without unduetoxicity, irritation, allergic response, and the like, and arecommensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, Berge et al.,describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein byreference. Pharmaceutically acceptable salts of the compounds describedherein include those derived from suitable inorganic and organic acidsand bases. Examples of pharmaceutically acceptable, nontoxic acidaddition salts are salts of an amino group formed with inorganic acidssuch as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuricacid, and perchloric acid or with organic acids such as acetic acid,oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, ormalonic acid or by using other methods known in the art such as ionexchange. Other pharmaceutically acceptable salts include adipate,alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate,borate, butyrate, camphorate, camphorsulfonate, citrate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptonate, glycerophosphate, gluconate,hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and thelike. Salts derived from appropriate bases include alkali metal,alkaline earth metal, ammonium and N⁺(C₁₋₄ alkyl)₄ ⁻ salts.Representative alkali or alkaline earth metal salts include sodium,lithium, potassium, calcium, magnesium, and the like. Furtherpharmaceutically acceptable salts include, when appropriate, nontoxicammonium, quaternary ammonium, and amine cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, lower alkyl sulfonate, and aryl sulfonate.

The term “solvate” refers to forms of the compound that are associatedwith a solvent, usually by a solvolysis reaction. This physicalassociation may include hydrogen bonding. Conventional solvents includewater, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and thelike. The compounds described herein may be prepared, e.g., incrystalline form, and may be solvated. Suitable solvates includepharmaceutically acceptable solvates and further include bothstoichiometric solvates and non-stoichiometric solvates. In certaininstances, the solvate will be capable of isolation, for example, whenone or more solvent molecules are incorporated in the crystal lattice ofa crystalline solid. “Solvate” encompasses both solution-phase andisolatable solvates. Representative solvates include hydrates,ethanolates, and methanolates.

The term “hydrate” refers to a compound that is associated with water.Typically, the number of the water molecules contained in a hydrate of acompound is in a definite ratio to the number of the compound moleculesin the hydrate. Therefore, a hydrate of a compound may be represented,for example, by the general formula R·x H₂O, wherein R is the compound,and x is a number greater than 0. A given compound may form more thanone type of hydrate, including, e.g., monohydrates (x is 1), lowerhydrates (x is a number greater than 0 and smaller than 1, e.g.,hemihydrates (R·0.5 H₂O)), and polyhydrates (x is a number greater than1, e.g., dihydrates (R·2 H₂O) and hexahydrates (R·6 H₂O)).

The term “tautomers” or “tautomeric” refers to two or moreinterconvertible compounds resulting from at least one formal migrationof a hydrogen atom and at least one change in valency (e.g., a singlebond to a double bond, a triple bond to a single bond, or vice versa).The exact ratio of the tautomers depends on several factors, includingtemperature, solvent, and pH. Tautomerizations (i.e., the reactionproviding a tautomeric pair) may catalyzed by acid or base. Exemplarytautomerizations include keto-to-enol, amide-to-imide, lactam-to-lactim,enamine-to-imine, and enamine-to-(a different enamine) tautomerizations.

It is also to be understood that compounds that have the same molecularformula but differ in the nature or sequence of bonding of their atomsor the arrangement of their atoms in space are termed “isomers”. Isomersthat differ in the arrangement of their atoms in space are termed“stereoisomers”.

Stereoisomers that are not mirror images of one another are termed“diastereomers” and those that are non-superimposable mirror images ofeach other are termed “enantiomers”. When a compound has an asymmetriccenter, for example, it is bonded to four different groups, a pair ofenantiomers is possible. An enantiomer can be characterized by theabsolute configuration of its asymmetric center and is described by theR- and S-sequencing rules of Cahn and Prelog, or by the manner in whichthe molecule rotates the plane of polarized light and designated asdextrorotatory or levorotatory (i.e., as (+) or (−)-isomersrespectively). A chiral compound can exist as either individualenantiomer or as a mixture thereof. A mixture containing equalproportions of the enantiomers is called a “racemic mixture”.

The term “polymorphs” refers to a crystalline form of a compound (or asalt, hydrate, or solvate thereof) in a particular crystal packingarrangement. All polymorphs have the same elemental composition.Different crystalline forms usually have different X-ray diffractionpatterns, infrared spectra, melting points, density, hardness, crystalshape, optical and electrical properties, stability, and solubility.Recrystallization solvent, rate of crystallization, storage temperature,and other factors may cause one crystal form to dominate. Variouspolymorphs of a compound can be prepared by crystallization underdifferent conditions.

The term “prodrugs” refers to compounds that have cleavable groups andbecome by solvolysis or under physiological conditions the compoundsdescribed herein, which are pharmaceutically active in vivo. Suchexamples include, but are not limited to, choline ester derivatives andthe like, N-alkylmorpholine esters and the like. Other derivatives ofthe compounds described herein have activity in both their acid and acidderivative forms, but in the acid sensitive form often offer advantagesof solubility, tissue compatibility, or delayed release in the mammalianorganism (see, Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24,Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well knownto practitioners of the art, such as, for example, esters prepared byreaction of the parent acid with a suitable alcohol, or amides preparedby reaction of the parent acid compound with a substituted orunsubstituted amine, or acid anhydrides, or mixed anhydrides. Simplealiphatic or aromatic esters, amides, and anhydrides derived from acidicgroups pendant on the compounds described herein are particularprodrugs. In some cases it is desirable to prepare double ester typeprodrugs such as (acyloxy)alkyl esters or((alkoxycarbonyl)oxy)alkylesters. C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈alkynyl, aryl, C₇-C₁₂ substituted aryl, and C₇-C₁₂ arylalkyl esters ofthe compounds described herein may be preferred.

The term “inhibition”, “inhibiting”, “inhibit,” or “inhibitor” refer tothe ability of a compound to reduce, slow, halt or prevent activity of aparticular biological process (e.g., activity of an IDO enzyme in a cellrelative to vehicle.

When a compound, pharmaceutical composition, method, use, or kit isreferred to as “selectively,” “specifically,” or “competitively”inhibiting the activity of an IDO enzyme, the compound, pharmaceuticalcomposition, method, use, or kit inhibits the activity of the IDO enzymeto a greater extent (e.g., not less than about 2-fold, not less thanabout 5-fold, not less than about 10-fold, not less than about 30-fold,not less than about 100-fold, not less than about 1,000-fold, or notless than about 10,000-fold) than the activity of at least one proteinthat is different from the IDO enzyme.

The term “aberrant activity” refers to activity deviating from normalactivity. The term “increased activity” refers to activity higher thannormal activity.

The terms “composition” and “formulation” are used interchangeably.

A “subject” to which administration is contemplated refers to a human(i.e., male or female of any age group, e.g., pediatric subject (e.g.,infant, child, or adolescent) or adult subject (e.g., young adult,middle-aged adult, or senior adult)). A “patient” refers to a humansubject in need of treatment of a disease.

The term “biological sample” refers to any sample including tissuesamples (such as tissue sections and needle biopsies of a tissue); cellsamples (e.g., cytological smears (such as Pap or blood smears) orsamples of cells obtained by microdissection); samples of wholeorganisms (such as samples of yeasts or bacteria); or cell fractions,fragments or organelles (such as obtained by lysing cells and separatingthe components thereof by centrifugation or otherwise). Other examplesof biological samples include blood, serum, urine, semen, fecal matter,cerebrospinal fluid, interstitial fluid, mucous, tears, sweat, pus,biopsied tissue (e.g., obtained by a surgical biopsy or needle biopsy),nipple aspirates, milk, vaginal fluid, saliva, swabs (such as buccalswabs), or any material containing biomolecules that is derived from afirst biological sample.

The terms “administer,” “administering,” or “administration” refers toimplanting, absorbing, ingesting, injecting, inhaling, or otherwiseintroducing a compound described herein, or a composition thereof, in oron a subject.

The terms “treatment,” “treat,” and “treating” refer to reversing,alleviating, delaying the onset of, or inhibiting the progress of adisease described herein. In some embodiments, treatment may beadministered after one or more signs or symptoms of the disease havedeveloped or have been observed. In other embodiments, treatment may beadministered in the absence of signs or symptoms of the disease. Forexample, treatment may be administered to a susceptible subject prior tothe onset of symptoms (e.g., in light of a history of symptoms and/or inlight of exposure to a pathogen) to delay or prevent disease occurrence.Treatment may also be continued after symptoms have resolved, forexample, to delay or prevent recurrence.

The terms “condition,” “disease,” and “disorder” are usedinterchangeably.

An “effective amount” of a compound described herein refers to an amountsufficient to elicit the desired biological response, i.e., treating thecondition. As will be appreciated by those of ordinary skill in thisart, the effective amount of a compound described herein may varydepending on such factors as the desired biological endpoint, thepharmacokinetics of the compound, the condition being treated, the modeof administration, and the age and health of the subject. In certainembodiments, an effective amount is a therapeutically effective amount.In certain embodiments, an effective amount is a prophylactic treatment.In certain embodiments, an effective amount is the amount of a compounddescribed herein in a single dose. In certain embodiments, an effectiveamount is the combined amounts of a compound described herein inmultiple doses.

A “therapeutically effective amount” of a compound described herein isan amount sufficient to provide a therapeutic benefit in the treatmentof a condition or to delay or minimize one or more symptoms associatedwith the condition. A therapeutically effective amount of a compoundmeans an amount of therapeutic agent, alone or in combination with othertherapies, which provides a therapeutic benefit in the treatment of thecondition. The term “therapeutically effective amount” can encompass anamount that improves overall therapy, reduces or avoids symptoms, signs,or causes of the condition, and/or enhances the therapeutic efficacy ofanother therapeutic agent.

A “prophylactically effective amount” of a compound described herein isan amount sufficient to prevent a condition, or one or more symptomsassociated with the condition or prevent its recurrence. Aprophylactically effective amount of a compound means an amount of atherapeutic agent, alone or in combination with other agents, whichprovides a prophylactic benefit in the prevention of the condition. Theterm “prophylactically effective amount” can encompass an amount thatimproves overall prophylaxis or enhances the prophylactic efficacy ofanother prophylactic agent.

A “proliferative disease” refers to a disease that occurs due toabnormal growth or extension by the multiplication of cells (Walker,Cambridge Dictionary of Biology; Cambridge University Press: Cambridge,UK, 1990). A proliferative disease may be associated with: 1) thepathological proliferation of normally quiescent cells; 2) thepathological migration of cells from their normal location (e.g.,metastasis of neoplastic cells); 3) the pathological expression ofproteolytic enzymes such as the matrix metalloproteinases (e.g.,collagenases, gelatinases, and elastases); or 4) the pathologicalangiogenesis as in proliferative retinopathy and tumor metastasis.Exemplary proliferative diseases include cancers (i.e., “malignantneoplasms”), benign neoplasms, angiogenesis, inflammatory diseases, andautoimmune diseases.

The terms “neoplasm” and “tumor” are used herein interchangeably andrefer to an abnormal mass of tissue wherein the growth of the masssurpasses and is not coordinated with the growth of a normal tissue. Aneoplasm or tumor may be “benign” or “malignant,” depending on thefollowing characteristics: degree of cellular differentiation (includingmorphology and functionality), rate of growth, local invasion, andmetastasis. A “benign neoplasm” is generally well differentiated, hascharacteristically slower growth than a malignant neoplasm, and remainslocalized to the site of origin. In addition, a benign neoplasm does nothave the capacity to infiltrate, invade, or metastasize to distantsites. Exemplary benign neoplasms include, but are not limited to,lipoma, chondroma, adenomas, acrochordon, senile angiomas, seborrheickeratoses, lentigos, and sebaceous hyperplasias. In some cases, certain“benign” tumors may later give rise to malignant neoplasms, which mayresult from additional genetic changes in a subpopulation of the tumor'sneoplastic cells, and these tumors are referred to as “pre-malignantneoplasms.” An exemplary pre-malignant neoplasm is a teratoma. Incontrast, a “malignant neoplasm” is generally poorly differentiated(anaplasia) and has characteristically rapid growth accompanied byprogressive infiltration, invasion, and destruction of the surroundingtissue. Furthermore, a malignant neoplasm generally has the capacity tometastasize to distant sites. The term “metastasis,” “metastatic,” or“metastasize” refers to the spread or migration of cancerous cells froma primary or original tumor to another organ or tissue and is typicallyidentifiable by the presence of a “secondary tumor” or “secondary cellmass” of the tissue type of the primary or original tumor and not ofthat of the organ or tissue in which the secondary (metastatic) tumor islocated. For example, a prostate cancer that has migrated to bone issaid to be metastasized prostate cancer and includes cancerous prostatecancer cells growing in bone tissue.

The term “cancer” refers to a class of diseases characterized by thedevelopment of abnormal cells that proliferate uncontrollably and havethe ability to infiltrate and destroy normal body tissues. See, e.g.,Stedman's Medical Dictionary, 25th ed.; Hensyl ed.; Williams & Wilkins:Philadelphia, 1990. Exemplary cancers include, but are not limited to,hematological malignancies. Additional exemplary cancers include, butare not limited to, acoustic neuroma; adenocarcinoma; adrenal glandcancer; anal cancer; angiosarcoma (e.g., lymphangiosarcoma,lymphangioendotheliosarcoma, hemangiosarcoma); appendix cancer; benignmonoclonal gammopathy; biliary cancer (e.g., cholangiocarcinoma);bladder cancer; breast cancer (e.g., adenocarcinoma of the breast,papillary carcinoma of the breast, mammary cancer, medullary carcinomaof the breast); brain cancer (e.g., meningioma, glioblastomas, glioma(e.g., astrocytoma, oligodendroglioma), medulloblastoma); bronchuscancer; carcinoid tumor; cervical cancer (e.g., cervicaladenocarcinoma); choriocarcinoma; chordoma; craniopharyngioma;colorectal cancer (e.g., colon cancer, rectal cancer, colorectaladenocarcinoma); connective tissue cancer; epithelial carcinoma;ependymoma; endotheliosarcoma (e.g., Kaposi's sarcoma, multipleidiopathic hemorrhagic sarcoma); endometrial cancer (e.g., uterinecancer, uterine sarcoma); esophageal cancer (e.g., adenocarcinoma of theesophagus, Barrett's adenocarcinoma); Ewing's sarcoma; ocular cancer(e.g., intraocular melanoma, retinoblastoma); familiarhypereosinophilia; gall bladder cancer; gastric cancer (e.g., stomachadenocarcinoma); gastrointestinal stromal tumor (GIST); germ cellcancer; head and neck cancer (e.g., head and neck squamous cellcarcinoma, oral cancer (e.g., oral squamous cell carcinoma), throatcancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngealcancer, oropharyngeal cancer)); heavy chain disease (e.g., alpha chaindisease, gamma chain disease, mu chain disease; hemangioblastoma;hypopharynx cancer; inflammatory myofibroblastic tumors; immunocyticamyloidosis; kidney cancer (e.g., nephroblastoma a.k.a. Wilms' tumor,renal cell carcinoma); liver cancer (e.g., hepatocellular cancer (HCC),malignant hepatoma); lung cancer (e.g., bronchogenic carcinoma, smallcell lung cancer (SCLC), non-small cell lung cancer (NSCLC),adenocarcinoma of the lung); leiomyosarcoma (LMS); mastocytosis (e.g.,systemic mastocytosis); muscle cancer; myelodysplastic syndrome (MDS);mesothelioma; myeloproliferative disorder (MPD) (e.g., polycythemia vera(PV), essential thrombocytosis (ET), agnogenic myeloid metaplasia (AMM)a.k.a. myelofibrosis (MF), chronic idiopathic myelofibrosis, chronicmyelocytic leukemia (CML), chronic neutrophilic leukemia (CNL),hypereosinophilic syndrome (HES)); neuroblastoma; neurofibroma (e.g.,neurofibromatosis (NF) type 1 or type 2, schwannomatosis);neuroendocrine cancer (e.g., gastroenteropancreatic neuroendoctrinetumor (GEP-NET), carcinoid tumor); osteosarcoma (e.g., bone cancer);ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma,ovarian adenocarcinoma); papillary adenocarcinoma; pancreatic cancer(e.g., pancreatic andenocarcinoma, intraductal papillary mucinousneoplasm (IPMN), Islet cell tumors); penile cancer (e.g., Paget'sdisease of the penis and scrotum); pinealoma; primitive neuroectodermaltumor (PNT); plasma cell neoplasia; paraneoplastic syndromes;intraepithelial neoplasms; prostate cancer (e.g., prostateadenocarcinoma); rectal cancer; rhabdomyosarcoma; salivary gland cancer;skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA),melanoma, basal cell carcinoma (BCC)); small bowel cancer (e.g.,appendix cancer); soft tissue sarcoma (e.g., malignant fibroushistiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor(MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma); sebaceous glandcarcinoma; small intestine cancer; sweat gland carcinoma; synovioma;testicular cancer (e.g., seminoma, testicular embryonal carcinoma);thyroid cancer (e.g., papillary carcinoma of the thyroid, papillarythyroid carcinoma (PTC), medullary thyroid cancer); urethral cancer;vaginal cancer; and vulvar cancer (e.g., Paget's disease of the vulva).

DETAILED DESCRIPTION

The present disclosure provides indoleamine 2,3-dioxygenase (IDO)inhibitors, for example, the compounds of Formula (I). The compoundsdescribed herein are useful in treating and/or preventing proliferativediseases (e.g., cancer) via the inhibition of IDO and inhibition oftryptophan catabolism resulting in reduction of the kynurenine level.Exemplary IDO inhibiting compounds described herein successfullydemonstrated in vitro potency and in vivo efficacy. Moreover, thesecompounds showed better potency, and/or lower human hepatocyte clearancecompared to other IDO inhibitors known in the art, e.g., INCB-24360 andothers disclosed in WO2014150677 and WO2014150646. Also provided in thepresent disclosure are pharmaceutical compositions, kits, methods ofusing the IDO inhibitors described herein for treating proliferativediseases such as cancer.

IDO Inhibiting Compounds

One aspect of the present disclosure relates to the IDO inhibitingcompounds as described herein, as well as their pharmaceuticallyacceptable salts, solvates, hydrates, polymorphs, co-crystals,tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs.These compounds are useful in treating and/or preventing proliferativediseases in a subject.

In certain embodiments, a compound described herein is of Formula (I):

in which R¹—R⁶, W, Y, and Q are as described herein, or pharmaceuticallyacceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer,stereoisomer, isotopically labeled derivative, or prodrug thereof.

Formula (I) includes a linker W connecting substituents R¹, R², and R³with the aromatic ring containing Y. In some embodiments, W can be —O—.In some embodiments, W can be —S—. In some embodiments, W can be a bond.

Further, Formula (I) includes a linker Q connecting substituent R⁶ withthe —NH— linker attached to the aromatic ring containing Y. In someembodiments, Q can be —C(═O)NH—. In some embodiments, Q can be a bond.In some embodiments, -Q(R⁶) can be

In Formula (I), Y is in an aromatic ring. In some embodiments, Y is—CR⁸═, in which R⁸ is as defined wherein. In some embodiments, R⁸ can behydrogen. In some embodiments, R⁸ can be halogen (e.g., F, Cl, Br, orI). In some embodiments, R⁸ can be —CN. In some embodiments, R⁸ can be—OH. In some embodiments, R⁸ can be substituted or unsubstituted C₁₋₆alkyl (e.g., methyl, ethyl, propyl or butyl). In some embodiments, R⁸can be substituted or unsubstituted C₁₋₆ alkoxy (e.g., substituted orunsubstituted methoxy, or ethoxy). In one example, Y can be —CH═.

In some embodiments, R¹ in Formula (I) can be —C(═O)OH. In someembodiments, R¹ can be substituted or unsubstituted heterocyclyl (e.g.,substituted or unsubstituted, 3- to 9-membered, monocyclic heterocyclylcomprising zero, one, or two double bonds in the heterocyclic ringsystem, wherein one, two, three, or four atoms in the heterocyclic ringsystem are independently nitrogen, oxygen, or sulfur). In someembodiments, R¹ can be substituted or unsubstituted heteroaryl (e.g.,substituted or unsubstituted, 5- to 6-membered, monocyclic heteroarylwherein one, two, three, or four atoms in the heteroaryl ring system areindependently nitrogen, oxygen, or sulfur). In some embodiments, R¹ issubstituted or unsubstituted 5-membered heteroaryl. In certainembodiments, R¹ is substituted or unsubstituted 6-membered heteroaryl.In some embodiments, R¹ can be of the formula:

In some embodiments, R¹ can be —NHSO₂R⁹ or —C(═O)NHSO₂R⁹, in which R⁹ isas defined herein. In some embodiments, R⁹ can be hydrogen. In someembodiments, R⁹ can be substituted or unsubstituted C₁₋₆ alkyl (e.g.,methyl, ethyl, propyl or butyl). In some embodiments, R⁹ can besubstituted or unsubstituted C₂-C₆ alkenyl.

In some embodiments, R¹ can be —C(═O)NHC(═O)OR¹⁰ or —SO₂NHC(═O)R¹⁰, inwhich R¹⁰ is as defined herein. In some embodiments, R¹⁰ can behydrogen. In some embodiments, R¹⁰ can be substituted or unsubstitutedC₁₋₆ alkyl (e.g., methyl, ethyl, propyl or butyl). In some embodiments,R¹⁰ can be substituted or unsubstituted C₂-C₆ alkenyl.

In some embodiments, R¹ is —C(═O)OR¹⁰, wherein R¹⁰ is as defined herein.For example, R¹ can be optionally substituted —C(═O)O—C₁₋₆ alkyl.

In some embodiments, R² and/or R³ in Formula (I) can be hydrogen. Insome embodiments, R² and/or R³ can be halogen (e.g., F, Cl, Br, or I).In some embodiments, R² and/or R³ can be substituted or unsubstitutedC₁₋₆ alkyl (e.g., substituted or unsubstituted, methyl, ethyl, propyl orbutyl). In some embodiments, R² and/or R³ can be substituted orunsubstituted C₁₋₆ alkoxy (e.g., substituted or unsubstituted methoxy,or ethoxy).

In some embodiments, R² and R³ can be joined to form a substituted orunsubstituted, monocyclic or bicyclic, 3- to 8-membered carbocyclicring. In some embodiments, R² and R³ can be joined to form a substitutedor unsubstituted, monocyclic or bicyclic, 3- to 6-membered carbocyclicring (e.g., substituted or unsubstituted, cyclopropyl, cyclobutyl,cyclopentyl, or cyclohexyl). In some embodiments, R² and R³ can bejoined to form a substituted or unsubstituted cyclopropyl ring. In someembodiments, R² and R³ can be joined to form an unsubstitutedcyclopropyl ring. In some embodiments, R² and R³ can be joined to form asubstituted or unsubstituted cyclobutyl ring. In some embodiments, R²and R³ can be joined to form an unsubstituted cyclobutyl ring. In someembodiments, R² and R³ can be joined to form a substituted cyclobutylring. In some embodiments, R² and R³ can be joined to form a substitutedcyclobutyl ring of the formula:

In some embodiments, R² and R³ can be joined to form a substituted orunsubstituted cyclopentyl ring. In some embodiments, R² and R³ can bejoined to form an unsubstituted cyclopentyl ring. In some embodiments,R² and R³ can be joined to form a substituted or unsubstituted,monocyclic or bicyclic, 3- to 8-membered heterocyclic ring. In someembodiments, R² and R³ can be joined to form a substituted orunsubstituted, 3- to 9-membered heterocyclic ring (e.g., substituted orunsubstituted, 5- to 9-membered, monocyclic heterocyclic ring comprisingzero, one, or two double bonds in the heterocyclic ring system, whereinone, two, or three atoms in the heterocyclic ring system areindependently nitrogen, oxygen, or sulfur). In some embodiments, R² andR³ can be joined to form a substituted or unsubstitutedtetrahydropyranyl ring.

In some embodiments, R⁴ and/or R⁵ can be hydrogen. In some embodiments,R⁴ and/or R⁵ can be substituted or unsubstituted C₁₋₆ alkyl (e.g.,substituted or unsubstituted, methyl, ethyl, propyl or butyl). In someembodiments, R⁴ and/or R⁵ can be substituted methyl. In someembodiments, R⁴ and/or R⁵ can be unsubstituted methyl. In someembodiments, R⁴ and/or R⁵ can be substituted ethyl. In some embodiments,R⁴ and/or R⁵ can be unsubstituted ethyl. In some embodiments, R⁴ and/orR⁵ can be propyl. In some embodiments, R⁴ and/or R⁵ can be unsubstitutedisopropyl. In some embodiments, R⁴ and/or R⁵ can be isobutyl. In someembodiments, R⁴ and/or R⁵ can be of the formula:

wherein R can be substituted or unsubstituted C₁₋₆ alkyl. In someembodiments, R can be substituted or unsubstituted, methyl, ethyl,propyl or butyl. In some embodiments, R can be —CF₃. In someembodiments, R⁴ and/or R⁵ can be substituted or unsubstituted C₂-C₆alkenyl. In some embodiments, R⁴ and/or R⁵ can be substituted orunsubstituted C₅-C₈ cycloalkenyl. In some embodiments, R⁴ and/or R⁵ canbe substituted or unsubstituted C₂-C₁₀ alkynyl (e.g., substituted orunsubstituted, propynyl or butynyl). In some embodiments, R⁴ and/or R⁵can be substituted or unsubstituted aryl (e.g., phenyl, or benzyl). Insome embodiments, R⁴ can be of the formula:

In some embodiments, R⁴ and/or R⁵ can be of the formula:

In some embodiments, R⁴ and/or R⁵ can be substituted or unsubstitutedC₁-C₆ alkoxy (e.g., substituted or unsubstituted methoxy, or ethoxy). Insome embodiments, R⁴ and/or R⁵ can be substituted or unsubstituted C₃-C₈cycloalkyl (e.g., substituted or unsubstituted, cyclopropyl, cyclobutyl,cyclopentyl, or cyclohexyl). In some embodiments, R⁴ and/or R⁵ can be ofthe formula:

In some embodiments, R⁴ and/or R⁵ can be substituted or unsubstituted 3-to 12-membered heterocyclyl (e.g., substituted or unsubstituted, 3- to12-membered, monocyclic or bicyclic heterocyclyl comprising zero, one,or two double bonds in the heterocyclic ring system, wherein one, two,or three atoms in the heterocyclic ring system are independentlynitrogen, oxygen, or sulfur). In some embodiments, R⁴ and/or R⁵ can beof the formula:

In some embodiments, R⁴ and/or R⁵ can be substituted or unsubstituted,5- to 6-membered monocyclic heteroaryl, wherein one, two, three, or fouratoms in the heteroaryl ring system are independently nitrogen, oxygen,or sulfur). In some embodiments, R⁴ and/or R⁵ can be substituted orunsubstituted 8- to 10-membered bicyclic heteroaryl, wherein one, two,three, or four atoms in the heteroaryl ring system are independentlynitrogen, oxygen, or sulfur. In some embodiments, R⁴ and/or R⁵ can besubstituted or unsubstituted aryl (C₁-C₆ alkyl). In some embodiments, R⁴and/or R⁵ can be arylsulfonyl.

In some embodiments, R⁴ and R⁵ are independently one of the following:

In some embodiments, R⁴ and R⁵ are independently one of the following:

In some embodiments, R⁴ and R⁵ may be joined together with the N theyare attached to to form optionally substituted, monocyclic or bicyclic,heterocyclyl. In some embodiments, R⁴ and R⁵ may be joined together withthe N they are attached to to form optionally substituted 5- to7-membered heterocyclyl. In some embodiments, R⁴ and R⁵ may be joinedtogether with the N they are attached to to form optionally substituted6-membered heterocyclyl. In some embodiments, R⁴ and R⁵ may be joinedtogether with the N they are attached to to form optionally substituted6-membered heterocyclyl containing one or two heteroatoms independentlyselected from the group consisting of N, S, and O. In certainembodiments, R⁴ and R⁵ may be joined together with the N they areattached to to form an optionally substituted piperidine. In certainembodiments, R⁴ and R⁵ may be joined together with the N they areattached to to form an optionally substituted morpholine. For example,in certain embodiments, R⁴ and R⁵ may be joined together with the N theyare attached to to form one of the following:

In some embodiments, R⁶ in Formula (I) can be substituted orunsubstituted C₁₋₆ alkyl (e.g., substituted or unsubstituted, methyl,ethyl, propyl or butyl). In some embodiments, R⁶ can be isopropyl. Insome embodiments, R⁶ can be substituted methyl. In some embodiments, R⁶can be

In some embodiments, R⁶ can be substituted or unsubstituted C₃-C₈cycloalkyl (e.g., substituted or unsubstituted, cyclopropyl, cyclobutyl,cyclopentyl, or cyclohexyl). In some embodiments, R⁶ can be

In some embodiments, R⁶ can be substituted or unsubstituted benzoyl. Insome embodiments, R⁶ can be substituted or unsubstituted C₂-C₆ alkenyl.In some embodiments, R⁶ can be substituted or unsubstituted C₂-C₆alkynyl. In some embodiments, R⁶ can be substituted or unsubstitutedC₅-C₈ cycloalkenyl. In some embodiments, R⁶ can be substituted orunsubstituted aryl (e.g., phenyl, or benzyl). In some embodiments, R⁶can be substituted or unsubstituted benzyl. In some embodiments, R⁶ canbe of the formula:

wherein R^(6A) can be hydrogen, substituted or unsubstituted C₁-C₆alkyl, halogen, —CN, —OR^(6a), or substituted or unsubstituted sulfonylgroup, wherein R^(6a) can be hydrogen, or substituted or unsubstitutedC₁-C₆ alkyl; and k can be 0, 1, or 2. In some embodiments, R^(6a) can besubstituted or unsubstituted, C₁-C₆ alkyl (e.g., methyl, ethyl, propylor butyl). In some embodiments, R^(6A) can be halogen (e.g., F, Cl, Br,or I). In some embodiments, R^(6a) can be —CN. In some embodiments, kcan be 0. In some embodiments, k can be 1. In some embodiments, k can be2.

In some embodiments, R⁶ can be of the formula:

In some embodiments, R⁶ can be substituted or unsubstituted 4- to7-membered (e.g., 4, 5, 6, or 7) monocyclic heterocyclyl, comprisingzero, one, or two double bonds in the heterocyclic ring system, whereinone, two, or three atoms in the heterocyclic ring system areindependently nitrogen, oxygen, or sulfur. In some embodiments, R⁶ canbe

In some embodiments, R⁶ can be substituted or unsubstituted 7- to10-membered bicyclic heterocyclyl, comprising zero, one, or two doublebonds in the heterocyclic ring system, wherein one, two, or three atomsin the heterocyclic ring system are independently nitrogen, oxygen, orsulfur. In some embodiments, R⁶ can be substituted or unsubstituted 5-to 6-membered monocyclic heteroaryl, wherein one, two, three, or fouratoms in the heteroaryl ring system are independently nitrogen, oxygen,or sulfur. In some embodiments, R⁶ can be of the formula:

In some embodiments, R⁶ can be of the formula:

In some embodiments, R⁶ can be substituted or unsubstituted 8- to10-membered bicyclic heteroaryl, wherein one, two, three, or four atomsin the heteroaryl ring system are independently nitrogen, oxygen, orsulfur. In some embodiments, R⁶ can be of the formula:

In some embodiments, R⁶ can be substituted or unsubstituted C₁-C₆ alkoxy(e.g., substituted or unsubstituted methoxy, or ethoxy). In someembodiments, R⁶ can be substituted or unsubstituted aryloxy. In someembodiments, R⁶ can be —C(═O)R⁷, in which R⁷ is as defined herein. Insome embodiments, R⁶ can be

In some embodiments, the compound of Formula (I) can be of one of thefollowing formulae: Formula (II), Formula (III), Formula (IV), Formula(V), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In some embodiments, the compound of Formula (II) can be of the formulaof compounds 1-30, 59, 62-67, 83, 85, 90, compounds described herein, ora pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In some embodiments, the compound of Formula (III) can be of the formulaof compounds 31-35, compounds described herein, or a pharmaceuticallyacceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer,stereoisomer, isotopically labeled derivative, or prodrug thereof.

In some embodiments, the compound of Formula (IV) can be of the formulaof compounds 36-46, or a pharmaceutically acceptable salt, solvate,hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopicallylabeled derivative, or prodrug thereof.

In some embodiments, the compound of Formula (V) can be of compounds47-58, 60-61, 68-82, 84, 86-89, 91-125, and 126-128 described herein, ora pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

Exemplary IDO inhibitory compounds as described herein and theircharacterization are provided in Table 1 below:

TABLE 1 Characterization of the compounds of Formula (I) Compound No.Structure [M + H]⁺ ¹H-NMR  51

443.3 H-NMR (400 MHz, CD₃OD, ppm): δ 7.45 (d, J = 2.0 Hz, 1H), 7.21-7.19(m, 2H), 7.08-7.04 (m, 3H), 6.90 (dd, J = 2.0 Hz, 8.0 Hz, 1H), 2.57-2.55(m, 6H), 1.79-1.62 (m, 8H), 0.86 (d, J = 6.4 Hz, 12H).  52

455.2 HNMR: (400 MHz, DMSO d6, ppm): δ 11.80 (brs, 1H), 6.78 (d, J = 8.8Hz, 2H), 6.65 (d, J = 8.0 Hz, 1H), 6.60-659 (m, 2H), 6.57 (s, 1H), 6.55(s, 1H), 6.32 (dd, J1 = 8.0 Hz, J2 = 2.0 Hz, 1H), 2.30 (d, J = 6.8 Hz,2H), 2.21- 2.14 (m, 2H), 2.08-2.05 (m, 1H), 1.92-1.87 (m, 2H), 1.47-1.38(m, 1H), 1.35-1.30 (m, 1H), 1.26 (d, J = 11.6 Hz, 2H), 1.17-1.16 (m,2H), 0.98 (s, 1H), 0.89-0.77 (m, 3H), 0.50- 0.49 (m, 3H), 0.34 (d, J =6.8 Hz, 6H).  53

465.3 HNMR: (400 MHz, DMSO d₆, ppm): δ 7.06 (d, J = 8.0 Hz, 1H), 6.98(d, J = 8.8 Hz, 2H), 6.89 (d, J = 1.6 Hz, 1H), 6.84 (d, J = 8.8 Hz, 2H),6.76 (s, 1H), 6.61 (dd, J1 = 8.0 Hz, J2 = 1.6 Hz, 1H), 3.95 (q, J = 7.2Hz, 2H), 2.74 (d, J = 4.8 Hz, 2H), 2.61-2.54 (m, 2H), 2.51 (s, 1H),2.31-2.26 (m, 2H), 1.84-1.80 (m, 1H), 1.79-1.77 (m, 3H), 1.66-1.63 (m,2H), 1.47 (s, 1H), 1.35- 1.28 (m, 2H), 1.27 (t, J = 7.2 Hz, 3H), 1.19(s, 1H), 1.07-0.95 (m, 3H), 0.78 (d, J = 6.8 Hz, 6H).  54

423.1 HNMR: (400 MHz, DMSO d₆, ppm): δ 12.30 (s, 1H), 8.58 (s, 1H), 8.45(s, 2H), 7.27 (s, 1H), 7.11 (d, J = 8.0 Hz, 1H), 7.06 (d, J = 2.0 Hz,1H), 6.87 (dd, J1 = 8.0 Hz, J2 = 2.0 Hz, 1H), 2.74 (d, J = 6.4 Hz, 2H),2.66-2.57 (m, 3H), 2.37-2.32 (m, 2H), 1.92-1.85 (m, 1H), 1.81- 1.72 (m,1H), 1.67-1.59 (m, 4H), 1.41-1.40 (m, 1H), 1.38-1.31 (m, 1H), 1.27-1.20(m, 2H), 0.97-0.92 (m, 3H), 0.78 (d, J = 6.4 Hz, 6H).  55

467.2 HNMR: (400 MHz, DMSO d₆, ppm): δ 8.37 (s, 2H), 7.09 (d, J = 8.4Hz, 1H), 6.89 (s, 1H), 6.79 (d, J = 2.0 Hz, 1H), 6.69 (dd, J1 = 8.0 Hz,J2 = 2.0 Hz, 1H), 4.26 (q, J = 7.2 Hz, 2H), 2.75- 2.73 (m, 2H),2.61-2.52 (m, 3H), 2.32-2.27 (m, 2H), 1.88-1.69 (m, 4H), 1.65-1.63 (m,2H), 1.47-1.46 (m, 1H), 1.35-1.22 (m, 6H), 1.07-0.95 (m, 3H), 0.78 (d, J= 6.8 Hz, 6H).  56

446.2 HNMR: (400 MHz, DMSO d₆, ppm): δ 7.57 (s, 1H), 7.52 (d, J = 8.8Hz, 2H), 7.10-7.07 (m, 2H), 6.96-6.92 (m, 3H), 2.72 (d, J = 6.4 Hz, 2H),2.66-2.54 (m, 3H), 2.38-2.29 (m, 2H), 1.92-1.83 (m, 1H), 1.81-1.71 (m,1H), 1.58 (t, J = 12 Hz, 4H), 1.39-1.32 (m, 2H), 1.27-1.21 (m, 2H),0.93-0.91 (m, 1H), 0.87-0.82 (m, 2H), 0.77 (d, J = 6.4 Hz, 6H).  57

457.1 HNMR: (400 MHz, DMSO d₆, ppm): δ 12.26 (brs, 1H), 7.23 (d, J = 8.8Hz, 2H), 7.16-7.13 (m, 2H), 7.06-7.04 (m, 3H), 6.77 (dd, J = 8.0 Hz, J =2.0 Hz, 1H), 3.78-3.75 (m, 2H), 3.05 (t, J = 10.8 Hz, 2H), 2.81-2.73 (m,3H), 2.65-2.59 (m, 2H), 2.37-2.30 (m, 2H), 1.87-1.82 (m, 1H), 1.77-1.74(m, 1H), 1.61-1.58 (m, 2H), 1.52-1.43 (m, 2H), 1.34-1.31 (m, 1H), 0.78(d, J = 6.8 Hz, 6H).  58

469.1 HNMR: (400 MHz, DMSO d₆, ppm): δ 12.33 (brs, 1H), 9.65 (s, 1H),8.29 (d, J = 2.0 Hz, 1H), 7.89 (dd, J = 8.8 Hz, J = 5.2 Hz, 2H), 7.42(t, J = 8.8 Hz, 2H), 7.32 (d, J = 8.4 Hz, 1H), 7.01 (dd, J = 8.4 Hz, J =2.0 Hz, 1H), 3.78-3.75 (m, 2H), 3.17-3.12 (m 2H), 2.88-2.80 (m, 3H),2.71-2.65 (m, 2H), 2.41-2.34 (m, 2H), 1.95-1.89 (m, 1H), 1.80-1.75 (m,1H), 1.60- 1.57 (m, 2H), 1.50-1.41 (m, 2H), 1.32-1.26 (m, 1H), 0.77 (d,J = 6.4 Hz, 6H). 59A

431.3 Chiral HPLC [Column: IA, 100 mm, 4.6 mm, 0.6 mL/min, Mobile Phase:hexane (0.1% TFA)/IPA; Gradient: 5% IPA; Detector: 254 nm], Retentiontime = 10.98 mm, ¹H-NMR (300 MHz, CDCl₃, ppm) δ 8.54 (s, 1 H), 8.14 (s,1 H), 7.45 (s, 1 H), 7.15 (d, J = 8.1 Hz, 1 H), 7.04 (d, J = 7.8 Hz, 1H), 6.09 (s, 1H), 3.51 (t, J = 8.1 Hz, 1 H), 2.61 (d, J = 6 Hz, 4 H),2.19-2.10 (m, 2 H), 1.89-1.80 (m, 2 H), 1.73 (s, 2 H), 0.96-0.91 (m, 15H). 59B

431.3 Chiral HPLC [Column: IA, 100 mm, 4.6 mm, 0.6 mL/min, Mobile Phase:hexane (0.1% TFA)/IPA; Gradient: 5% IPA; Detector: 254 nm], Retentiontime = 13.14 min. ¹H-NMR (300 MHz, CDCl₃, ppm) δ 8.54 (s, 1 H), 8.14 (s,1 H), 7.45 (s, 1 H), 7.15 (d, J = 8.1 Hz, 1 H), 7.04 (d, J = 7.8 Hz, 1H), 6.09 (s, 1H), 3.51 (t, J = 8.1 Hz, 1 H), 2.61 (d, J = 6 Hz, 4 H),2.19-2.10 (m, 2 H), 1.89-1.80 (m, 2 H), 1.73 (s, 2 H), 0.96-0.89 (m, 15H) 60A

461.2 Chiral HPLC [Column: AD, 100 mm, 4.6 mm, 0.6 mL/min, Mobile Phase:hexane (0.1% TFA)/EtOH; Gradient: 20% EtOH; Detector: 254 nm], Retentiontime = 3.24 min. ¹H-NMR (300 MHz, CDCl₃, ppm) δ 7.79 (d, J = 8.7 Hz,2H), 7.45-7.36 (m, 1H), 7.23-7.10 (m, 3H), 7.02-6.85 (m, 1H), 3.46 (t, J= 7.8 Hz, 1H), 3.06 (s, 3H), 2.86-2.37 (m, 3H), 2.21-2.00 (m, 1H),1.93-1.51 (m, 3H), 1.0.3- 0.51 (m, 16H). 60B

461.2 Chiral HPLC [Column: AD, 100 mm, 4.6 mm, 0.6 mL/min, Mobile Phase:hexane (0.1% TFA)/EtOH; Gradient: 20% EtOH; Detector: 254 nm], Retentiontime = 3.69 min. ¹H-NMR (300 MHz, CDCl₃, ppm) δ 7.79 (d, J = 8.7 Hz,2H), 7.45-7.36 (m, 1H), 7.23-7.10 (m, 3H), 7.02-6.85 (m, 1H), 3.45 (t, J= 7.8 Hz, 1H), 3.06 (s, 3H), 2.86-2.40 (m, 3H), 2.21-2.00 (m, 1H),1.93-1.56 (m, 3H), 1.03- 0.57 (m, 16H).  61

408.4 1HNMR (DMSO-d₆, 300 MHz, ppm) δ 7.78 (s, 1H), 7.54 (d, J = 8.7 Hz,2H), 7.17-7.11 (m, 2H), 6.98-6.90 (m, 3H), 3.33 (t, J = 7.5 Hz, 1H),2.65 (d, J = 7.2 Hz, 4H), 1.97-1.83 (m, 1H), 1.72-1.54 (m, 3H),0.84-0.75 (m, 15H). 61A

408.4 Chiral HPLC [Column: IA-3, 100 mm, 4.6 mm, 0.6 mL/min, MobilePhase: hexane (0.1% TFA)/IPA; Gradient: 20% IPA; Detector: 254 nm],Retention time = 3.30 min. H-NMR (300 MHz, CDClC₃, ppm), δ 7.53- 7.42(m, 3H), 7.38 (d, J = 1.5 Hz, 1H), 7.23- 7.13 (m, 1H), 7.08 (d, J = 8.7Hz, 2H), 6.93 (d, J = 7.8 Hz, 1H), 3.47 (t, J = 7.5 Hz, 1H), 2.68-2.45(m, 3H), 2.16 -2.06 (m, 1H), 1.86- 1.68 (m, 4H), 0.97 (t, J = 7.2 Hz,3H), 0.89- 0.86 (m, 12H). 61B

408.4 Chiral HPLC [Column: IA-3, 100 mm, 4.6 mm, 0.6 mL/min, MobilePhase: hexane (0.1% TFA)/IPA; Gradient: 20% IPA; Detector: 254 nm],Retention time = 2.81 min. H-NMR (300 MHz, CDClC₃, ppm): δ7.53- 7.42 (m,2H), 7.38 (d, J = 1.5 Hz, 1H), 7.18 (d, J = 8.4 Hz, 1H), 7.07 (d, J =8.7 Hz, 2H), 6.93 (dd, J = 8.1, J = 1.5 Hz, 1H), 3.47 (t, J = 7.8 Hz,1H), 2.68-2.45 (m, 3H), 2.16-2.06 (m, 1H), 1.86-1.68 (m, 4H), 0.97 (t, J= 7.2 Hz, 3H), 0.89-0.86 (m, 12H). 62A

488.3 Chiral HPLC [Column: IA, 100 mm, 4.6 mm, 0.6 mL/min, Mobile Phase:hexane (0.1% TFA)/EtOH; Gradient: 30% EtOH; Detector: 254 nm], Retentiontime = 2.73 min. ¹HNMR: (300 MHz, DMSO-d₆, ppm): δ 12.18 (brs, 1 H),9.34 (s, 1 H), 8.17 (s, 1 H), 7.91-7.85 (m, 2 H), 7.34-7.26 (m, 1 H),7.14- 7.02 (m, 2 H), 6.87 (d, J = 6.3 Hz, 1 H), 3.31- 3.27 (m, 1 H),2.87-2.75 (m, 2 H), 2.54-2.43 (m, 1 H), 1.97-1.86 (m, 3 H), 1.70-1.57(m, 3 H), 1.53-1.50 (m, J = 9, 1 H), 1.34-0.97 (m, 6 H), 0.86-0.80 (m, 9H). 62B

488.3 Chiral HPLC [Column: IA, 100 mm, 4.6 mm, 0.6 mL/min, Mobile Phase:hexane (0.1% TFA)/EtOH; Gradient: 30% EtOH; Detector: 254 nm], Retentiontime = 3.17 min. ¹HNMR: (300 MHz, DMSO-d₆, ppm): δ 9.36 (s, 1 H), 8.17(s, 1 H), 7.94-7.85 (m, 2 H), 7.34-7.27 (m, 1 H), 7.14-7.05 (m, 2 H),6.88 (d, J = 6.3 Hz, 1 H), 3.33-3.28 (m, 1 H), 2.77-2.76 (m, 2 H),2.54-2.50 (m, 1 H), 1.95- 1.86 (m, 3 H), 1.70-1.49 (m, 4 H), 1.34- 1.03(m, 6 H), 0.86-0.80 (m, 9 H). 63A

457.3 Chiral HPLC [Column: AD, 100 mm, 4.6 mm, 0.6 mL/min, Mobile Phase:hexane (0.1% TFA)/EtOH; Gradient: 10% EtOH; Detector: 254 nm], Retentiontime = 2.98 min. ¹HNMR: (300 MHz, DMSO-d₆, ppm): δ 11.25 (brs, 1 H),8.34 (s, 1 H), 8.02 (d, J = 1.8 Hz, 1 H), 7.18 (d, J = 8.1 Hz, 1 H),6.91 (d, J = 8.4 Hz, 1 H), 5.99 (s, 1 H), 3.35-3.30 (m, 1 H), 2.78-2.73(m, 2 H), 2.17 (s, 3 H), 1.98-1.89 (m, 3 H), 1.71-1.58 (m, 3 H),1.53-1.50 (m, 1 H), 1.31-0.98 (m, 6 H), 0.91- 0.80 (m, 9 H). 63B

457.3 Chiral HPLC [Column: AD, 100 mm, 4.6 mm, 0.6 mL/min, Mobile Phase:hexane (0.1%TFA)/EtOH; Gradient: 10% EtOH; Detector: 254 nm], Retentiontime = 3.39 min. ¹HNMR: (300 MHz, DMSO-d₆, ppm): δ 11.26 (s, 1 H), 8.34(s, 1 H), 8.02 (d, J = 1.5 Hz, 1 H), 7.17 (d, J = 8.1 Hz, 1 H), 6.91 (d,J = 8.4 Hz, 1 H), 5.99 (s, 1 H), 3.35-3.30 (m, 1 H), 2.78-2.73 (m, 2 H),2.17 (s, 3 H), 1.98- 1.89 (m, 3 H), 1.71-1.58 (m, 3 H), 1.54-1.50 (m, 1H), 1.32-1.00 (m, 6 H), 0.86-0.80 (m, 9 H). 64A

454.3 Chiral HPLC [Column: AD, 100 mm, 4.6 mm, 0.6 mL/min, Mobile Phase:hexane (0.1% TFA)/IPA; Gradient: 30% IPA; Detector: 254 nm], Retentiontime = 2.16 min. ¹HNMR: (300 MHz, DMSO-d₆, ppm): δ 9.96 (s, 1 H), 8.93(s, 2 H), 8.82 (s, 1 H), 8.27 (s, 1 H), 8.04 (s, 1 H), 7.19 (d, J = 8.4Hz, 1H), 6.91-6.89 (m 1 H), 3.36-3.31 (m, 1 H), 2.81-2.73 (s, 2 H),2.60-2.51 (m, 1 H), 1.99- 1.92 (m, 3 H), 1.71-1.50 (m, 4 H), 1.34-1.01(m, 6 H), 0.86-0.67 (m, 9 H). 64B

454.3 Chiral HPLC [Column: AD, 100 mm, 4.6 mm, 0.6 mL/min, Mobile Phase:hexane (0.1% TFA)/IPA; Gradient: 30% IPA; Detector: 254 nm], Retentiontime = 2.68 min. ¹HNMR: (300 MHz, DMSO-d₆, ppm): δ 12.26 (brs, 1 H),9.95 (s, 1 H), 8.93 (s, 2 H), 8.82 (s, 1 H), 8.27 (s, 1 H), 8.03 (d, J =1.8 Hz, 1H), 7.19 (d, J = 8.4 Hz, 1 H), 6.92-6.89 (dd, J = 1.8, 8.4 Hz,2 H), 2.96-2.73 (m, 2H), 2.57-2.51 (m, 1 H), 2.01-1.92 (m, 3 H), 1.71-1.50 (m, 4 H), 1.34-0.92 (m, 6 H), 0.87-0.68 (m, 9 H).  65

490.4 ¹HNMR (300 MHz, CD₃OD, ppm) δ 8.06 (m, 1H), 7.89-7.81 (m, 1H),7.24-6.98 (m, 4H), 3.97-3.93 (m, 2H), 3.54-3.38 (m, 3H), 2.88- 2.84 (m,3H), 2.13-2.04 (m, 1H), 1.85- 1.65 (m, 5H), 1.47-1.39 (m, 1H), 0.97-0.89(m, 9H). 65A

490.4 Chiral HPLC [Column: AD-3, 100 mm, 4.6 mm, 0.6 mL/min, MobilePhase: hexane (0.1% TFA)/IPA; Gradient: 10% IPA; Detector: 254 nm],Retention time = 11.59 min. H-NMR (300 MHz, CD₃OD, ppm): δ 8.02 (s, 1H),7.86-7.78 (m, 1H), 7.22-7.10 (m, 1H), 7.06-6.96 (m, 3H), 3.92 (d, J =8.7 Hz, 2H), 3.68-3.31 (m, 2H), 2.99-2.69 (m, 3H), 2.30- 1.95 (m, 1H),1.93-1.50 (m, 5H), 1.50-1.20 (m, 2H), 1.15-0.70 (m, 9H)). 65B

490.4 Chiral HPLC [Column: AD-3, 100 mm, 4.6 mm, 0.6 mL/min, MobilePhase: hexane (0.1% TFA)/IPA; Gradient: 10% IPA; Detector: 254 nm],Retention time = 13.85 min. H-NMR (300 MHz, CD₃OD, ppm): δ 8.02 (s, 1H),7.86-7.78 (m, 1H), 7.21-7.11 (m, 1H), 7.04-6.93 (m, 3H), 3.93 (d, J =9.0 Hz, 2H), 3.58-3.31 (m, 2H), 3.00-2.70 (m, 3H), 2.28- 1.95 (m, 1H),1.93-1.50 (m, 5H), 1.50-1.40 (m, 1H), 1.40-1.20 (m, 1H), 1.10-0.75 (m,9H). 66A

456.2 Chiral HPLC [Column: IC, 100 mm, 4.6 mm, 0.6 mL/min, Mobile Phase:hexane (0.1% TFA)/IPA; Gradient: 10% IPA; Detector: 254 nm], Retentiontime = 23.48 min. ¹H-NMR (300 MHz, CD₃OD, ppm): δ 8.99 (s, 2H), 8.79 (s,1H), 8.16 (d, J = 1.5 Hz, 1H), 7.26 (d, J = 8.4 Hz, 1H), 7.05 (dd, J =8.4 Hz, 1.8 Hz, 1H), 3.95-3.90 (m, 2H), 3.53-3.37 (m, 3H), 3.07-2.85 (m,3H), 2.01-2.03 (m, 1H), 1.83-1.71 (m, 3H), 1.67-1.54 (m, 2H), 1.46-1.36(m, 1H), 0.96-0.86 (m, 9H). 66B

456.2 Chiral HPLC [Column: IC, 100 mm, 4.6 mm, 0.6 mL/min, Mobile Phase:hexane (0.1% TFA)/IPA; Gradient: 10% IPA; Detector 254 nm], Retentiontime = 18.91 min. ¹HNMR (300 MHz, CD₃OD, ppm): δ 8.99 (s, 2H), 8.79 (s,1H), 8.16 (d, J = 1.5 Hz, 1H), 7.26 (d, J = 8.4 Hz, 1H), 7.05 (dd, J =8.4 Hz, 1.8 Hz, 1H), 3.95-3.90 (m, 2H), 3.53-3.37 (m, 3H), 3.07-2.85 (m,3H), 2.01-2.03 (m, 1H), 1.83-1.71 (m, 3H), 1.67-1.54 (m, 2H), 1.46-1.36(m, 1H), 0.96-0.86 (m, 9H).  67

459.3 ¹HNMR (300 MHz, CD₃OD, ppm): δ 8.17 (s, 1H), 7.27 (d, J = 9.0 Hz,1H), 7.05 (d, J = 9.0 Hz, 1H), 6.08 (s, 1H), 3.94 (d, J = 12.0 Hz, 1H),3.47-3.38 (m, 3H), 2.86 (m, 3H), 2.26 (s, 3H), 2.15-2.05 (m, 1H),1.85-1.76 (m, 3H), 1.68-1.56 (m, 2H), 1.43-1.38 (m, 1H), 0.95 (t, J =7.2 Hz, 3H), 0.88 (d, J = 6.6 Hz, 6H). 68A

445.2 Chiral HPLC [Column: AD, 100 mm, 4.6 mm, 0.6 mL/min, Mobile Phase:hexane (0.1% TFA)/IPA; Gradient: 5% IPA; Detector: 254 nm], Retentiontime = 6.12 min. ¹HNMR: (300 MHz, DMSO-d₆, ppm): δ 7.33-7.07 (m, 7 H),6.81-6.79 (m, 1 H), 3.81- 3.79 (m, 2 H), 3.35-3.30 (m, 1 H), 3.14-3.10(m, 2 H), 2.96-2.74 (m, 3 H), 1.95-1.86 (m, 1 H), 1.66-1.32 (m, 5 H),0.86-0.80 (m, 9 H). 68B

445.2 Chiral HPLC [Column: AD, 100 mm, 4.6 mm, 0.6 mL/min, Mobile Phase:hexane (0.1% TFA)/IPA; Gradient: 5% IPA; Detector: 254 nm], Retentiontime = 6.40 min. ¹HNMR: (300 MHz, DMSO-d₆, ppm): δ 7.33-7.07 (m, 7 H),6.82-6.79 (m, 1 H), 3.81- 3.78 (m, 2 H), 3.35-3.30 (m, 1 H), 3.14-3.06(m, 2 H), 2.96-2.73 (m, 3 H), 1.95-1.86 (m, 1 H), 1.66-1.23 (m, 5 H),0.86-0.80 (m, 9 H).  69

447.2 ¹HNMR: (300 MHz, DMSO-d₆, ppm): δ 7.43-7.29 (m, 2 H), 7.20-7.17(m, 2 H), 7.07- 7.02 (m, 2 H), 6.76 (d, J = 7.8 Hz, 1 H), 3.83- 3.76 (m,2 H), 3.45-3.12 (m, 4 H), 2.93-2.79 (m, 3 H), 1.94-1.82 (m, 1 H),1.67-1.32 (m, 5 H), 0.89-0.73 (m, 9 H). 70A

436.2 Chiral HPLC [Column: IA, 100 mm, 4.6 mm, 0.6 mL/min, Mobile Phase:hexane (0.1% TFA)/EtOH; Gradient: 10% EtOH; Detector: 254 nm], Retentiontime = 5.61 min. ¹HNMR: (300 MHz, DMSO-d₆, ppm): δ 7.76 (s, 1 H), 7.57(d, J = 8.4 Hz, 2 H), 7.30-7.13 (m, 2 H), 7.08-6.90 (m, 3 H), 3.78- 3.76(m, 2 H), 3.40-3.35 (m, 1 H), 3.04-2.91 (m, 2 H), 2.77-2.69 (m, 2 H),1.97-1.86 (m, 1 H), 1.69-1.31 (m, 7 H), 0.84-0.79 (m, 9 H). 70B

436.2 Chiral HPLC [Column: IA, 100 mm, 4.6 mm, 0.6 mL/min, Mobile Phase:hexane (0.1% TFA)/EtOH; Gradient: 10% EtOH; Detector: 254 nm], Retentiontime = 6.10 min. ¹HNMR: (300 MHz, DMSO-d₆, ppm): δ 7.76 (s, 1 H), 7.57(d, J = 8.4 Hz, 2 H), 7.30- 7.12 (m, 2 H), 7.04-6.90 (m, 3 H), 3.78 (m,2 H), 3.40-3.35 (m, 1 H), 3.04-2.91 (m, 2 H), 2.77-2.69 (m, 2 H),1.97-1.86 (m, 1 H), 1.69- 1.31 (m, 7 H), 0.84-0.79 (m, 9 H).  71

491.2 ¹HNMR (300 MHz, CD₃OD, ppm): δ 7.22- 7.19 (m, 2H), 7.10 (d, J =8.7 Hz, 1H), 7.03 (d, J = 2.4 Hz, 1H), 6.90-6.83 (m, 2H), 3.92 (dd, J =3.9 Hz, J = 11.1 Hz, 2H), 3.40-3.25 (m, 3H), 2.95-2.86 (m, 3H),2.11-1.95 (m, 1H), 1.81-1.41 (m, 6H), 0.95-0.88 (m, 9H). 71A

491.2 Chiral HPLC [Column: YMC-SB, 150 mm, 4.6 mm, 1 mL/min, MobilePhase: hexane (0.1% TFA)/EtOH; Gradient: 5% EtOH; Detector: 254 nm],Retention time = 6.29 min. ¹HNMR (300 MHz, CD₃OD, ppm): δ 7.17- 7.15 (m,2 H), 7.05 (d, J = 8.7 Hz, 1H), 6.99 (d, J = 2.1 Hz, 1 H), 6.86-6.78 (m,2H), 3.90- 3.85 (m, 2H), 3.36-3.21 (m, 3H), 2.90-2.86 (m, 1 H), 2.83 (d,J = 3.9 Hz, 2 H), 2.08-1.99 (m, 1H), 1.75-1.55 (m, 5 H), 1.48-1.40 (m,1H), 0.92-0.85 (m, 9H). 71B

491.2 Chiral HPLC [Column: YMC-SB, 150 mm, 4.6 mm, 1 mL/min, MobilePhase: hexane (0.1% TFA)/EtOH; Gradient: 5% EtOH; Detector: 254 nm],Retention time = 6.78 min. H-NMR (300 MHz, CD₃OD, ppm): δ 7.19- 7.16 (m,2 H), 7.07 (d, J = 8.7 Hz, 1H), 7.00 (d, J = 2.1 Hz, 1 H), 6.87-6.80 (m,2H), 3.90- 3.85 (m, 2H), 3.36-3.21 (m, 3H), 2.90-2.86 (m, 1 H), 2.83 (d,J = 3.9 Hz, 2 H), 2.08-1.99 (m, 1H), 1.75-1.55 (m, 5 H), 1.47-1.40 (m,1H), 0.93-0.86 (m, 9H).  72

448.2 ¹HNMR: (400 MHz, DMSO-d6, ppm): δ 7.72 (s, 1H), 7.53 (d, J = 8.8Hz, 2H), 7.15 (d, J = 8.4 Hz, 1H), 7.10 (d, J = 2.0 Hz, 1H), 6.98 (d, J= 8.8 Hz, 2H), 6.94 (dd, J1 = 8.4 Hz, J2 = 2.0 Hz, 1H), 3.74 (d, J =11.2 Hz, 2H), 2.98- 2.92 (m, 2H), 2.88-2.85 (m, 1H), 2.72 (d, J = 6.8Hz, 2H), 2.66-2.60 (m, 2H), 2.37-2.32 (m, 2H), 1.90-1.83 (m, 1H),1.81-1.72 (m, 1H), 1.49 (s, 4H), 1.37-1.30 (m, 1H), 0.75 (d, J = 6.4 Hz,6H).  73

467.2 ¹HNMR: (400 MHz, DMSO-d6, ppm): δ 12.17 (brs, 1H), 7.10 (d, J =8.0 Hz, 1H), 7.01 (d, J = 8.8 Hz, 2H), 6.89-6.88 (m, 2H), 6.84 (d, J =8.8 Hz, 2H), 6.62 (dd, J1 = 8.0 Hz, J2 = 2.0 Hz, 1H), 3.95 (q, J = 6.8Hz, 2H), 3.80- 3.77 (m, 2H), 3.16-3.10 (m 2H), 2.81-2.74 (m, 3H),2.62-2.57 (m, 2H), 2.32-2.25 (m, 2H), 1.84-1.80 (m, 1H), 1.75-1.73 (m,1H), 1.71- 1.63 (m, 2H), 1.54-1.46 (m, 2H), 1.36-1.34 (m, 1H), 1.30-1.26(m, 3H), 0.80 (d, J = 6.8 Hz, 6H).  74

425.3 ¹HNMR: (400 MHz, DMSO-d6, ppm): δ 12.31 (s, 1H), 8.61 (s, 1H),8.50 (s, 2H), 7.41 (s, 1H), 7.17 (d, J = 8.0 Hz, 1H), 7.07 (d, J = 1.2Hz, 1H), 6.87-6.85 (m, 1H), 3.78-3.75 (m, 2H), 3.09-3.04 (m, 2H),2.91-2.86 (m, 1H), 2.74 (d, J = 6.8 Hz, 2H), 2.66-2.59 (m, 2H),2.38-2.31 (m, 2H), 1.94-1.83 (m, 1H), 1.80- 1.73 (m, 1H), 1.59-1.53 (m,2H), 1.55-1.44 (m, 2H), 1.35-1.30 (m, 1H), 0.78 (d, J = 6.8 Hz, 6H).  75

469.3 ¹HNMR: (400 MHz, DMSO-d6, ppm): δ 12.22 (s, 1H), 8.38 (s, 2H),7.13 (d, J = 8.0 Hz, 1H), 7.03 (s, 1H), 6.77 (s, 1H), 6.69 (d, J = 8.0Hz, 1H), 4.27 (q, J = 7.2 Hz, 2H), 3.79 (d, J = 8.0 Hz, 2H), 3.14 (t, J= 11.6 Hz, 2H), 2.84 (t, J = 11.2 Hz, 1H), 2.75 (d, J = 6.0 Hz, 2H),2.61-2.55 (m, 2H), 2.33-2.26 (m, 2H), 1.85- 1.80 (m, 1H), 1.77-1.65 (m,3H), 1.54-1.46 (m, 2H), 1.36-1.33 (m, 1H), 1.29 (t, J = 7.2 Hz, 3H),0.79 (d, J = 6.4 Hz, 6H).  76

444.2 ¹HNMR: (400 MHz, DMSO-d6, ppm): δ 12.28 (brs, 1H), 8.76 (s, 1H),7.94 (d, J = 2.0 Hz, 1H), 7.22 (d, J = 8.4 Hz, 1H), 6.84 (dd, J1 = 8.4Hz, J2 = 2.0 Hz, 1H), 6.48 (s, 1H), 3.80-3.77 (m, 2H), 3.14 (t, J = 11.2Hz, 2H), 2.85-2.70 (m, 3H), 2.67-2.64 (m, 2H), 2.41-2.34 (m, 2H), 2.18(s, 3H), 1.95- 1.74 (m, 2H), 1.69-1.60 (m, 2H), 1.48-1.38 (m, 2H),1.32-1.25 (m, 1H), 0.79 (d, J = 6.4 Hz, 6H).  77

501.3 ¹HNMR: (400 MHz, DMSO-d6, ppm): δ 12.31 (brs, 1H), 7.67-7.63 (m,3H), 7.17-7.14 (m, 2H), 7.07 (d, J = 8.8 Hz, 2H), 6.92 (dd, J1 = 8.4 Hz,J2 = 1.6 Hz, 1H), 3.74 (d, J = 10.8 Hz, 2H), 3.07 (s, 3H), 2.98 (t, J =10.0 Hz, 2H), 2.89-2.84 (m, 1H), 2.74 (d, J = 6.8 Hz, 2H), 2.67-2.60 (m,2H), 2.38-2.33 (m, 2H), 1.89-1.85 (m, 1H), 1.82-1.74 (m, 1H), 1.52-1.49(m, 4H), 1.39-1.30 (m, 1H), 0.77 (d, J = 6.4 Hz, 6H).  79

389.3 ¹HNMR: (400 MHz, DMSO-d6, ppm): δ 7.02 (d, J = 7.6 Hz, 1H),6.57-6.55 (m, 2H), 3.91 (dd, J1 = 11.2 Hz, J2 = 3.2 Hz, 2H), 3.61- 3.58(m, 1H), 3.32-3.26 (m, 1H), 3.26-3.21 (m, 1H), 2.96 (d, J = 9.2 Hz, 1H),2.78-2.71 (m, 3H), 2.58-2.42 (m, 3H), 1.96-1.37 (m, 7H), 1.21 (dd, J1 =36.0 Hz, J2 = 6.4 Hz, 6H), 0.83 (dd, J1 = 32.8 Hz, J2 = 6.4 Hz, 6H).  80

401.2 ¹HNMR: (400 MHz, DMSO-d6, ppm): δ 7.02 (d, J = 8.0 Hz, 1H),6.59-6.57 (m, 2H), 3.92 (d, J = 11.2 Hz, 2H), 3.36-3.23 (m, 2H), 3.08-2.98 (m, 2H), 2.84-2.71 (m, 4H), 2.59-2.53 (m, 1H), 2.49-2.42 (m, 2H),1.97-1.94 (m, 1H), 1.85-1.60 (m, 5H), 1.42-1.38 (m, 1H), 1.10-1.08 (m,1H), 0.83(dd, J1 = 29.6 Hz, J2 = 6.4 Hz, 6H), 0.51 (dd, J1 = 8.0 Hz, J2= 1.2 Hz, 2H), 0.23-0.20 (m, 2H).  81

430.3 ¹HNMR (300 MHz, CD₃OD, ppm): δ 7.10 (d, J = 8.0 Hz, 1H), 6.66-6.62(m, 2H), 3.92-3.90 (m, 2H), 3.69-3.64 (m, 1H), 3.45-3.39 (m, 2H),3.38-3.30 (m, 2H), 3.21-3.12 (m, 2H), 3.05-2.99 (m, 1H), 2.89-2.87 (m,1H), 2.76- 2.66 (m, 3H), 2.51-2.43 (m, 2H), 2.35-2.25 (m, 2H), 2.01-1.40(m, 9H), 0.88 (d, J = 6.4 Hz, 3H), 0.80 (d, J = 6.4 Hz, 3H).  82

512.3 ¹HNMR: (400 MHz, DMSO-d6, ppm): δ 12.15 (brs, 1H), 6.98 (d, J =8.0 Hz, 1H), 6.44- 6.41 (m, 2H), 4.84 (d, J = 8.4 Hz, 1H), 3.84- 3.78(m, 2H), 3.29-3.21 (m, 2H), 3.18- 3.11 (m, 4H), 2.90-2.82 (m, 3H),2.66-2.61 (m, 3H), 2.55-2.49 (m, 2H), 2.36-2.29 (m, 2H), 1.87-1.59 (m,6H), 1.52-1.38 (m, 3H), 1.27-1.20 (m, 2H), 0.80 (d, J = 6.4 Hz, 3H),0.74 (d, J = 6.4 Hz, 3H).  84

430.2 ¹HNMR: (400 MHz, DMSO-d6, ppm): δ 12.36 (brs, 1H), 7.84 (d, J =2.0 Hz, 1H), 7.40 (s, 1H), 7.18 (d, J = 2.0 Hz, 1H), 7.14 (d, J = 8.8Hz, 2H), 6.67 (d, J = 8.8 Hz, 2H), 3.02 (d, J = 7.2 Hz, 4H), 2.63-2.56(m 2H), 2.35-2.28 (m, 2H), 1.89-1.81 (m, 1H), 1.80-1.64 (m, 3H), 0.70(d, J = 6.8 Hz, 12H).  85

444.3 ¹HNMR: (400 MHz, DMSO-d6, ppm): δ 8.28 (d, J = 2.0 Hz, 1H), 8.01(d, J = 2.0 Hz, 1H), 6.03 (s, 1H), 2.91 (d, J = 7.2 Hz, 4H), 2.82- 2.75(m, 2H), 2.43-2.36 (m, 2H), 2.21 (s, 3H), 1.98-1.95 (m, 1H), 1.84-1.81(m, 1H), 1.74- 1.68 (m, 2H), 0.83 (d, J = 6.4 Hz, 12H).  86

449.3 ¹HNMR: (400 MHz, DMSO-d6, ppm): δ 12.30 (brs, 1H), 8.66 (s, 1H),8.53 (d, J = 2.0 Hz, 1H), 7.97 (d, J = 1.6 Hz, 1H), 7.87 (dd, J1 = 8.4Hz, J2 = 2.0 Hz, 1H), 7.21 (d, J = 8.4 Hz, 1H), 6.99-6.93 (m, 2H),3.79-3.75 (m, 2H), 3.09-3.04 (m 2H), 2.89-2.84 (m, 1H), 2.76 (d, J = 6.4Hz, 2H), 2.69-2.63 (m, 2H), 2.41-2.33 (m, 2H), 1.94-1.85 (m, 1H), 1.80-1.73 (m, 1H), 1.60-1.57 (m, 2H), 1.53-1.43 (m, 2H), 1.35-1.26 (m, 1H),0.77 (d, J = 6.8 Hz, 6H).  87

427.3 ¹HNMR (400 MHz, CD₃OD, ppm): δ 7.51 (s, 1H), 7.34 (s, 1H), 7.09(d, J = 8.0 Hz, 1H), 6.79 (d, J = 2.0 Hz, 1H), 6.67 (dd, J1 = 8.0 Hz, J2= 2.0 Hz, 1H), 3.90 (d, J = 11.2 Hz, 2H), 3.84 (s, 3H), 3.34-3.31 (m,2H), 2.86-2.67 (m, 5H), 2.43-2.36 (m, 2H), 1.92-1.83 (m, 1H), 1.82-1.42(m, 6H), 0.85 (s, 6H).  88

475.3 ¹HNMR: (400 MHz, DMSO-d6, ppm): δ 7.44 (d, J = 10.8 Hz, 1H),7.33-7.29 (m, 2H), 7.22- 7.17 (m, 2H), 7.03 (d, J = 1.6 Hz, 1H), 6.79(dd, J1 = 8.0 Hz, J2 = 1.6 Hz, 1H), 3.77 (d, J = 8.0 Hz, 2H), 3.11 (t, J= 11.6 Hz, 2H), 2.81- 2.76 (m, 3H), 2.66-2.60 (m, 2H), 2.38-2.33 (m,2H), 1.89-1.84 (m, 1H), 1.80-1.74 (m, 1H), 1.59-1.56 (m, 2H), 1.50-1.41(m, 2H), 1.33-1.26 (m, 1H), 0.78 (d, J = 6.4 Hz, 6H).  89

459.3 ¹HNMR (400 MHz, CD₃OD, ppm): δ 7.40- 7.34 (m, 1H), 7.18 (d, J =8.4 Hz, 1H), 7.07 (d, J = 2.0 Hz, 1H), 7.03-6.97 (m, 1H), 6.90-6.85 (m,1H), 6.82 (dd, J1 = 8.0 Hz, J2 = 1.6 Hz, 1H), 3.88 (dd, J1 = 11.2 Hz, J2= 3.6 Hz, 2H), 3.25- 3.22 (m, 2H), 2.88-2.83 (m, 3H), 2.77-2.70 (m, 2H),2.46-2.39 (m, 2H), 2.02-1.91 (m, 1H), 1.88-1.78 (m, 1H), 1.73-1.70 (m,2H), 1.66-1.56 (m, 2H), 1.47-1.37 (m, 1H), 0.85 (d, J = 6.4 Hz, 6H).  90

503.3 H-NMR: (400 MHz, DMSO-d₆, ppm): δ 9.48 (s, 1H), 8.19-8.14 (m, 2H),7.95-7.90 (m, 2H), 7.28-7.24 (m, 1H), 7.01-6.97 (m, 1H), 3.79 (d, J =8.8 Hz, 2H), 3.15-3.10 (m, 2H), 2.97-2.86 (m, 3H), 2.67-2.65 (m, 2H),2.21- 2.19(m, 2H), 1.88-1.82 (m, 1H), 1.65-1.51 (m, 5H), 1.27-1.24 (m,1H), 0.76 (d, J = 7.2 Hz, 6H).  91

449.3 H-NMR: (400 MHz, DMSO-d₆, ppm): δ 8.00- 7.97 (m, 2H), 7.49 (d, J =8.4 Hz, 2H), 7.37 (s, 1H), 6.78 (d, J = 8.4 Hz, 2H), 3.74 (d, J = 8.4Hz, 2H), 3.10-2.90 (m, 5H), 2.67-2.60 (m, 2H), 2.29-2.23 (m, 2H),1.86-1.72 (m, 2H), 1.56-1.34 (m, 5H), 0.74 (d, J = 6.4 Hz, 6H).  92

458.3 H-NMR (400 MHz, DMSO-d₆, ppm): δ 7.84 (d, J = 2.0 Hz, 1H), 7.30(d, J = 2.0 Hz, 1H), 7.19-7.17 (m, 3H), 6.88 (d, J = 8.8 Hz, 2H),3.77-3.73 (m, 2H), 3.10-2.90 (m, 5H), 2.64- 2.58 (m, 2H), 2.33-2.26 (m,2H), 1.89-1.72 (m, 2H), 1.61-1.51 (m, 2H), 1.44-1.37 (m, 3H), 0.76 (d, J= 7.6 Hz, 6H).  93

421.3 H-NMR (400 MHz, DMSO-d₆, ppm): δ 8.26 (s, 1H), 7.96 (d, J = 2.0Hz, 1H), 7.48 (d, J = 8.8 Hz, 2H), 7.21 (d, J = 2.4 Hz, 1H), 6.61 (d, J= 8.8 Hz, 2H), 3.09 (d, J = 6.8 Hz, 4H), 2.65- 2.58 (m, 2H), 2.37-2.30(m, 2H), 1.95-1.65 (m, 4H), 0.68 (d, J = 6.8 Hz, 12H).  94

447.3 H-NMR (400 MHz, DMSO-d₆, ppm): δ 8.51 (s, 2H), 7.86 (dd, J1 = 8.8Hz, J2 = 2.0 Hz, 1H), 7.83 (s, 1H), 7.15 (d, J = 8.4 Hz, 1H), 6.94- 6.90(m, 2H), 2.75 (d, J = 6.8 Hz, 2H), 2.68- 2.62 (m, 2H), 2.55-2.52 (m,1H), 2.38-2.33 (m, 2H), 1.92-1.84 (m, 1H), 1.78-1.73 (m, 1H), 1.69 (d, J= 11.6 Hz, 2H), 1.60-1.59 (m, 2H), 1.42-1.40 (m, 1H), 1.33-1.20 (m, 3H),0.93-0.90 (m, 3H), 0.77 (d, J = 6.4 Hz, 6H).  95

413.3 H-NMR (400 MHz, DMSO-d₆, ppm): δ 7.39 (s, 1H), 7.22-7.19 (m, 2H),7.15 (d, J = 8.0 Hz, 1H), 7.06-7.05 (m, 2H), 7.03 (s, 1H), 6.76 (dd, J₁= 8.4Hz, J₂ = 2.0 Hz, 1H), 3.13-3.07 (m, 1H), 2.74 (d, J = 6.4 Hz, 2H),2.65-2.59 (m, 2H), 2.37-2.29 (m, 2H), 1.91-1.82 (m, 1H), 1.80-1.70 (m,1H), 0.91 (d, J = 6.8 Hz, 6H), 0.69-0.59 (m, 1H), 0.26-0.22 (m, 2H),0.02- 0.01 (m, 2H).  96

429.3 H-NMR (400 MHz, CD₃OD, ppm): δ 7.23- 7.16 (m, 4H), 7.06-7.04 (m,2H), 6.83 (dd, J1 = 8.0 Hz, J2 = 2.0 Hz, 1H), 2.79-2.73 (m, 2H), 2.61(d, J = 7.2 Hz, 4H), 2.49-2.42 (m, 2H), 1.99-1.95 (m, 1H), 1.87-1.84 (m,1H), 1.74-1.68 (m, 2H), 0.89 (d, J = 6.4 Hz, 12H).  97

441.3 H-NMR (400 MHz, DMSO-d₆, ppm): δ 8.33 (s, 2H), 7.13 (d, J = 8.0Hz, 1H), 6.94 (s, 1H), 6.80 (d, J = 2.0 Hz, 1H), 6.73 (dd, J1 = 8.0 Hz,J2 = 2.0 Hz, 1H), 4.25 (q, J = 7.2 Hz, 2H), 2.60- 2.47 (m, 6H),2.33-2.25 (m, 2H), 1.86-1.58 (m, 4H), 1.28 (t, J = 7.2 Hz, 3H), 0.80 (d,J = 6.4 Hz, 12H).  98

425.3 H-NMR (400 MHz, DMSO-d₆, ppm): δ 8.38 (s, 2H), 7.20 (d, J = 8.0Hz, 1H), 6.94 (d, J = 2.0 Hz, 1H), 6.83 (dd, J1 = 8.0 Hz, J2 = 2.0 Hz,1H), 4.37 (q, J = 7.2 Hz, 2H), 3.25- 3.19 (m, 1H), 2.82 (d, J = 6.8 Hz,2H), 2.77- 2.70 (m, 2H), 2.46-2.38 (m, 2H), 2.00-1.93 (m, 1H), 1.86-1.79(m, 1H), 1.38 (t, J = 7.2 Hz, 3H), 1.02 (d, J = 6.4 Hz, 6H), 0.74-0.68(m, 1H), 0.31-0.26 (m, 2H), 0.02-0.00 (m, 2H).  99

406.3 H-NMR (400 MHz, DMSO-d₆, ppm): δ 7.57- 7.52 (m, 3H), 7.15 (s, 1H),7.08-7.00 (m, 3H), 6.89 (d, J = 7.6 Hz, 1H), 3.48 (s, 2H), 2.74-2.72 (m,2H), 2.60-2.50 (m, 1H), 1.64- 1.56 (m, 4H), 1.40-1.34 (m, 2H), 1.26-1.23(m, 2H), 0.90-0.80 (m, 3H), 0.77 (d, J = 6.8 Hz, 6H). 100

457.3 H-NMR (400 MHz, DMSO-d₆, ppm): δ 7.23 (s, 1H), 7.18 (t, J = 8.0Hz, 1H), 7.14 (d, J = 8.4 Hz, 1H), 7.08 (d, J = 1.6 Hz, 1H), 7.05 (s,1H), 6.97 (d, J = 8.0 Hz, 1H), 6.82-6.79 (m, 2H), 3.76 (dd, J1 = 11.2Hz, J2 = 3.2 Hz, 2H), 3.03 (t, J = 11.2 Hz, 2H), 2.85-2.79 (m, 1H), 2.73(d, J = 6.4 Hz, 2H), 2.66-2.59 (m, 2H), 2.37-2.29 (m, 2H), 1.89-1.83 (m,1H), 1.80- 1.72 (m, 1H), 1.59-1.57 (m, 2H), 1.52-1.42 (m, 2H), 1.36-1.29(m, 1H), 0.77 (d, J = 6.8 Hz, 6H). 101

475.3 H-NMR (400 MHz, DMSO-d₆, ppm): δ 7.33- 7.29 (m, 2H), 7.14 (d, J =8.4 Hz, 1H), 7.07 (d, J = 2.0 Hz, 1H), 6.96 (dd, J1 = 12.4 Hz, J2 = 2.4Hz, 1H), 6.86-6.84 (m, 2H), 3.76 (dd, J1 = 10.8 Hz, J2 = 2.8 Hz, 2H),3.02 (t, J = 6.4 Hz, 2H), 2.86-2.80 (m, 1H), 2.73 (d, J = 6.4 Hz, 2H),2.66-2.59 (m, 2H), 2.37-2.30 (m, 2H), 1.92-1.83 (m, 1H), 1.81-1.71 (m,1H), 1.57- 1.42 (m, 4H), 1.35-1.29 (m, 1H), 0.76 (d, J = 6.4 Hz, 6H).102

458.3 H-NMR (400 MHz, DMSO-d₆, ppm): δ 8.18 (s, 1H), 8.15 (d, J = 2.8Hz, 1H), 8.10 (d, J = 2.0 Hz, 1H), 7.64 (dd, J1 = 8.8 Hz, J2 = 2.8 Hz,1H), 7.18 (d, J = 8.4 Hz, 1H), 6.97 (d, J = 8.8 Hz, 1H), 6.82 (dd, J1 =8.0 Hz, J2 = 2.0 Hz, 1H), 3.79-3.76 (m, 2H), 3.10 (t, J = 10.8 Hz, 2H),2.83-2.80 (m, 1H), 2.76 (d, J = 6.8 Hz, 2H), 2.69-2.63 (m, 2H),2.40-2.34 (m, 2H), 1.92-1.86 (m, 1H), 1.84-1.71 (m, 1H), 1.64-1.62 (m,2H), 1.52-1.42 (m, 2H), 1.35-1.25 (m, 1H), 0.79 (d, J = 6.4 Hz, 6H). 103

491.2 H-NMR (400 MHz, DMSO-d₆, ppm): δ 12.31 (brs, 1H), 7.47 (s, 1H),7.15 (d, J = 8.0 Hz, 1H), 7.06 (d, J = 1.6 Hz, 1H), 6.94 (d, J = 1.2 Hz,2H), 6.90 (dd, J = 8.0 Hz, J = 1.6 Hz, 1H), 6.84 (s, 1H), 3.77 (d, J =10.8 Hz, 2H), 3.05-2.99 (m, 2H), 2.92-2.85 (m, 1H), 2.72 (d, J = 6.4 Hz,2H), 2.67-2.61 (m, 2H), 2.37- 2.30 (m, 2H), 1.91-1.84 (m, 1H), 1.80-1.74(m, 1H), 1.56-1.47 (m, 4H), 1.36-1.29 (m, 1H), 0.76 (d, J = 6.8 Hz, 6H).104

417.2 H-NMR (400 MHz, DMSO-d₆, ppm): δ 12.26 (brs, 1H), 7.24-7.20 (m,3H), 7.13-7.08 (m, 4H), 6.73 (d, J = 7.6 Hz, 1H), 3.76 (d, J = 10.8 Hz,2H), 3.45 (s, 2H), 3.06 (t, J = 11.2 Hz, 2H), 2.81-2.74 (m, 3H),1.62-1.59 (m, 2H), 1.51-1.43 (m, 2H), 1.36-1.31 (m, 1H), 0.78 (d, J =6.0 Hz, 6H). 105

430.3 H-NMR (400 MHz, DMSO-d₆, ppm): δ 12.22 (brs, 1H), 8.23 (s, 1H),8.17 (d, J = 2.8 Hz, 1H), 8.05 (d, J = 2.0 Hz, 1H), 7.65 (dd, J1 = 8.8Hz, J2 = 2.8 Hz, 1H), 7.20 (d, J = 8.0 Hz, 1H), 6.83 (dd, J1 = 8.0 Hz,J2 = 2.0 Hz, 1H), 6.79 (d, J = 8.8 Hz, 1H), 2.69-2.63 (m, 2H), 2.56 (d,J = 6.8 Hz, 4H), 2.40-2.32 (m, 2H), 1.88-1.86 (m, 1H), 1.77-1.76 (m,1H), 1.65- 1.58 (m, 2H), 0.83 (d, J = 6.8 Hz, 12H). 106

422.3 H-NMR (400 MHz, DMSO-d₆, ppm): δ 9.05 (s, 1H), 8.41 (d, J = 2.0Hz, 1H), 7.94 (d, J = 2.0 Hz, 1H), 7.84 (dd, J = 2.0 Hz, 8.8 Hz, 1H),7.55 (d, J = 2.0 Hz, 1H), 6.63 (d, J = 8.8 Hz, 1H), 3.09 (d, J = 6.8 Hz,4H), 2.66-2.60 (m, 2H), 2.38-2.31 (m, 2H), 1.93-1.68 (m, 4H), 0.70 (d, J= 6.4 Hz, 12H). 107

431.3 H-NMR (400 MHz, DMSO-d₆, ppm): δ 8.29 (s, 1H), 8.05 (d, J = 2.8Hz, 1H), 7.85 (d, J = 2.4 Hz, 1H), 7.79 (d, J = 2.4 Hz, 1H), 7.60 (dd, J= 2.8 Hz, 8.8 Hz, 1H), 6.70 (d, J = 8.8 Hz, 1H), 3.02 (d, J = 6.8 Hz,4H), 2.67-2.60 (m, 2H), 2.39-2.32 (m, 2H), 1.91-1.67 (m, 4H), 0.74 (d, J= 6.4 Hz, 12H). 108

405.3 H-NMR (400 MHz, DMSO-d₆, ppm): δ 8.90 (s, 1H), 8.52 (d, J = 2.4Hz, 1H), 7.96 (d, J = 1.6 Hz, 1H), 7.85 (dd, J1 = 2.4 Hz, J2 = 8.4 Hz,1H), 7.22 (d, J = 8.4 Hz, 1H), 6.97 (d, J = 8.4 Hz, 1H), 6.94-6.92 (dd,J1 = 2.0 Hz, J2 = 8.0 Hz, 1H), 3.16-3.10 (m, 1H), 2.75 (d, J = 6.8 Hz,2H), 2.69-2.63 (m, 2H), 2.40-2.33 (m, 2H), 1.93-1.84 (m, 1H), 1.82-1.72(m, 1H), 0.91 (d, J = 6.4 Hz, 6H), 0.63-0.59 (m, 1H), 0.26-0.21 (m, 2H),0.03-0.00 (m, 2H). 109

429.3 H-NMR (400 MHz, DMSO-d₆, ppm): δ 8.41 (s, 2H), 7.12-7.05 (m, 2H),6.84 (s, 1H), 6.66 (d, J = 7.2 Hz, 1H), 4.28 (q, J = 7.2 Hz,2H),3.81-3.78 (m, 2H), 3.41 (s, 2H), 3.14 (t, J = 11.6 Hz, 2H), 2.83-2.76(m, 3H), 1.72- 1.67 (m, 2H), 1.55-1.45 (m, 2H), 1.36-1.28 (m, 4H), 0.79(d, J = 6.8 Hz, 6H). 110

406.3 H-NMR (400 MHz, DMSO-d₆, ppm): δ 9.01 (s, 1H), 8.48 (d, J = 1.6Hz, 1H), 7.98 (d, J = 2.0 Hz, 1H), 7.87-7.85 (m, 2H), 6.79 (d, J = 9.2Hz, 1H), 3.64-3.60 (m, 1H), 2.98 (d, J = 6.4 Hz, 2H), 2.70-2.63 (m, 2H),2.47-2.35 (m, 2H), 1.93-1.79 (m, 2H), 0.91 (d, J = 6.4 Hz, 6H),0.81-0.76 (m, 1H), 0.29-0.25 (m, 2H), 0.02-0.00 (m, 2H). 111

415.2 H-NMR (400 MHz, DMSO-d₆, ppm): δ 8.48 (s, 1H), 8.11 (dd, J = 2.0Hz, 5.6 Hz, 2H), 7.91 (d, J = 2.0 Hz, 1H), 7.64 (dd, J = 2.4 Hz, 8.8 Hz,1H), 6.93 (d, J = 8.8 Hz, 1H), 3.58-3.55 (m, 1H), 2.99 (d, J = 6.4 Hz,2H), 2.70-2.64 (m, 2H), 2.47-2.36 (m, 2H), 1.96-1.77 (m, 2H), 0.96 (d, J= 6.8 Hz, 6H), 0.76-0.71 (m, 1H), 0.27-0.22 (m, 2H), 0.03-0.00 (m, 2H).112

404.3 H-NMR (400 MHz, DMSO-d₆, ppm): δ 8.01 (s, 1H), 7.51 (d, J = 7.6Hz, 2H), 7.17 (d, J = 8.4 Hz, 1H), 7.09 (s, 1H), 6.99 (d, J = 8.4 Hz,2H), 6.93 (d, J = 8.4 Hz, 1H), 3.21-3.14 (m, 1H), 2.74 (d, J = 6.0 Hz,2H), 2.66-2.60 (m, 2H), 2.37-2.32 (m, 2H), 1.90-1.83 (m, 1H), 1.81-1.75(m, 1H), 0.85 (d, J = 6.4 Hz, 6H), 0.74-0.67 (m, 1H), 0.28-0.26 (m, 2H),0.01- 0.00 (m, 2H). 113

414.2 H-NMR (400 MHz, DMSO-d₆, ppm): δ 8.41 (s, 1H), 8.14 (d, J = 2.4Hz, 1H), 8.07 (d, J = 2.0 Hz, 1H), 7.61 (dd, J1 = 2.4 Hz, J2 = 8.8 Hz,1H), 7.19 (d, J = 8.0 Hz, 1H), 6.97 (d, J = 8.8 Hz, 1H), 6.83-6.81 (dd,J1 = 2.0 Hz, J2 = 8.0 Hz, 1H), 3.12-3.05 (m, 1H), 2.75 (d, J = 6.8 Hz,2H), 2.69-2.62 (m, 2H), 2.39-2.35 (m, 2H), 1.92-1.84 (m, 1H), 1.81-1.71(m, 1H), 0.94 (d, J = 6.4 Hz, 6H), 0.62-0.58 (m, 1H), 0.23-0.21 (m, 2H),0.02-0.00 (m, 2H). 114

413.3 H-NMR (400 MHz, DMSO-d₆, ppm): δ 8.32 (s, 2H), 7.34 (s, 1H), 7.13(d, J = 8.4 Hz, 1H), 6.93 (d, J = 2.0 Hz, 1H), 6.81 (dd, J1 = 2.0 Hz, J2= 8.4 Hz, 1H), 4.25 (q, J = 7.2 Hz, 2H), 3.20- 3.14 (m, 1H), 2.74 (d, J= 6.8 Hz, 2H), 1.38 (s, 6H), 1.28 (t, J = 7.2 Hz, 3H), 0.90 (d, J = 6.4Hz, 6H), 0.69-0.64 (m, 1H), 0.27-0.23 (m, 2H), 0.02-0.01 (m, 2H). 115

430.2 H-NMR (400 MHz, DMSO-d₆, ppm): δ 12.22 (s, 1H), 8.36 (s, 1H),8.16-8.13 (m, 2H), 7.62 (dd, J = 8.8 Hz, J = 2.8 Hz, 1H), 7.15 (d, J =8.0 Hz, 1H), 7.05 (d, J = 8.8 Hz, 1H), 6.83-6.81 (m, 1H), 3.78-3.75 (m,2H), 3.15 (t, J = 11.2 Hz, 2H), 3.00-2.91 (m, 3H), 2.69-2.63(m, 2H),2.41-2.34 (m, 2H), 1.91-1.73 (m, 2H), 1.64- 1.62 (m, 2H), 1.45-1.35 (m,2H), 0.81-0.77 (m, 3H). 116

405.2 H-NMR (400 MHz, DMSO-d₆, ppm): δ 8.45 (s, 1H), 7.96 (s, 1H), 7.51(d, J = 8.8 Hz, 2H), 7.40 (s, 1H), 6.76 (d, J = 8.8 Hz, 2H), 3.87- 3.80(m, 1H), 2.98 (d, J = 6.0 Hz, 2H), 2.68- 2.61 (m, 2H), 2.42-2.34 (m,2H), 1.95-1.76 (m, 2H), 0.94-0.85 (m, 1H), 0.81 (d, J = 6.4 Hz, 6H),0.35-0.33 (m, 2H), 0.05-0.03 (m, 2H). 117

441.3 H-NMR (400 MHz, DMSO-d₆, ppm): δ 12.2 (brs, 1H), 8.38 (s, 2H),7.32 (s, 1H), 7.10 (d, J = 8.0 Hz, 1H), 6.80 (s, 1H), 6.70 (d, J = 8.0Hz, 1H), 4.29-4.24 (m, 2H), 3.78 (d, J = 11.2 Hz, 2H), 3.20-3.15 (m,2H), 3.02-2.93 (m, 3H), 2.62-2.56 (m, 2H), 2.34-2.27 (m, 2H), 1.87-1.62(m, 4H), 1.46-1.37 (m, 2H), 1.30- 1.27 (m, 3H), 0.83-0.80 (m, 3H). 118

421.2 H-NMR (400 MHz, DMSO-d₆, ppm): δ 8.89 (d, J = 6.4 Hz, 1H), 8.52(d, J = 2.0 Hz, 1H), 7.99-7.98 (m, 1H), 7.87 (dd, J = 8.8 Hz, J = 2.0Hz, 1H), 7.24 (s, 1H), 7.04 (d, J = 8.8 Hz, 1H), 6.98 (s, 1H), 3.77 (d,J = 9.6 Hz, 2H), 3.15- 3.04 (m, 5H), 2.70-2.63 (m, 2H), 2.41-2.33 (m,2H), 1.92-1.73 (m, 2H), 1.61-1.59 (m, 2H), 1.47-1.38 (m, 2H), 0.83-0.79(m, 3H). 119

422.2 H-NMR (400 MHz, DMSO-d₆, ppm): δ 9.01 (d, J = 9.6 Hz, 1H), 8.48(d, J = 2.0 Hz, 1H), 7.98-7.97 (m, 2H), 7.87 (dd, J = 8.8 Hz, J = 1.6Hz, 1H), 6.88 (d, J = 8.8 Hz, 1H), 3.78-3.76 (m, 3H), 3.17-3.05 (m, 4H),2.70-2.64 (m, 2H), 2.42-2.35 (m, 2H), 1.95-1.78 (m, 2H), 1.61- 1.54 (m,2H), 1.49-1.46 (m, 2H), 0.86-0.83 (m, 3H). 120

430.2 H-NMR (400 MHz, DMSO-d₆, ppm): δ 7.85 (d, J = 2.4 Hz, 1H), 7.51(s, 1H), 7.27 (d, J = 2.0 Hz, 1H), 7.18 (d, J = 8.8 Hz, 2H), 6.87 (d, J= 8.8 Hz, 2H), 3.78-3.75 (m, 2H), 3.52-3.45 (m, 1H), 3.15-3.07 (m, 4H),2.66-2.59 (m, 2H), 2.39-2.32 (m, 2H), 1.94-1.85 (m, 1H), 1.83-1.73 (m,1H), 1.58-1.48 (m, 2H), 1.45- 1.42 (m, 2H), 0.83 (t, J = 7.2 Hz, 3H).121

457.3 H-NMR (400 MHz, DMSO-d₆, ppm): δ 8.36 (s, 2H), 7.12 (d, J = 8.4Hz, 1H), 7.02 (s, 1H), 6.87 (d, J = 1.6 Hz, 1H), 6.77 (d, J = 7.6 Hz,1H), 4.26 (q, J1 = 7.2 Hz, 2H), 3.79-3.76 (dd, J1 = 3.2 Hz, J2 = 10.8Hz, 2H), 3.12 (t, J = 11.2 Hz, 2H), 2.86-2.83 (m, 1H), 2.75-2.73 (m,2H), 1.66-1.63 (m, 2H), 1.53-1.43 (m, 2H), 1.35 (s, 6H), 1.32-1.30 (m,1H), 1.28 (t, J = 7.2 Hz, 3H), 0.78 (d, J = 6.8 Hz, 6H). 122

470.3 H-NMR (400 MHz, DMSO-d₆, ppm): δ 8.31 (s, 2H), 7.76 (d, J = 2.0Hz, 1H), 7.16-7.13 (m, 2H), 4.27 (q, J = 7.2 Hz, 2H), 3.80 (d, J = 10.4Hz, 2H), 3.37-3.31 (m, 1H), 3.17-3.12 (m, 2H), 2.96 (d, J = 6.8 Hz, 2H),2.62-2.57 (m, 2H), 2.38-2.31 (m, 2H), 1.87-1.80 (m, 1H), 1.80-1.70 (m,1H), 1.62-1.53 (m, 4H), 1.40-1.30 (m, 1H), 1.30 (t, J = 7.2 Hz, 3H),0.79 (d, J = 6.4 Hz, 6H). 123

431.2 H-NMR (400 MHz, DMSO-d₆, ppm): δ 8.38 (s, 1H), 8.21 (d, J = 2.4Hz, 1H), 8.11 (d, J = 2.4 Hz, 1H), 7.89 (d, J = 2.4 Hz, 1H), 7.64 (dd, J= 2.4 Hz, 8.8 Hz, 1H), 6.99 (d, J = 8.8 Hz, 1H), 3.79-3.76 (m, 2H),3.38-3.35 (m, 1H), 3.17-3.09 (m, 4H), 2.70-2.64 (m, 2H), 2.46-2.36 (m,2H), 1.94-1.78 (m, 2H), 1.57- 1.52 (m, 4H), 0.82 (t, J = 6.8 Hz, 3H).124

442.3 H-NMR (400 MHz, DMSO-d₆, ppm): δ 8.26 (s, 2H), 7.79 (d, J = 2.0Hz, 1H), 7.42 (s, 1H), 7.09 (d, J = 2.0 Hz, 1H), 4.26 (q, J = 7.2 Hz,2H), 3.79-3.76 (m, 2H), 3.42-3.37 (m, 1H), 3.20-3.14 (m, 2H), 3.11 (q, J= 6.8 Hz, 2H), 2.64-2.58 (m, 2H), 2.39-2.31 (m, 2H), 1.89- 1.76 (m, 2H),1.53-1.48 (m, 4H), 1.27 (t, J = 7.2 Hz, 3H), 0.86 (t, J = 6.8 Hz, 3H).125

421.2 H-NMR (400 MHz, DMSO-d₆, ppm): δ 8.29 (s, 1H), 7.98 (d, J = 2.4Hz, 1H), 7.50 (d, J = 8.8 Hz, 2H), 7.33 (d, J = 2.4 Hz, 1H), 6.75 (d, J= 8.8 Hz, 2H), 3.77-3.74 (m, 2H), 3.63- 3.58 (m, 1H), 3.16 (q, J = 6.8Hz, 2H), 3.08- 3.02 (m, 2H), 2.67-2.60 (m, 2H), 2.40-2.33 (m, 2H),1.93-1.77 (m, 2H), 1.62-1.52 (m, 2H), 1.36-1.34 (m, 2H), 0.86 (t, J =6.8 Hz, 3H). 126

474.1 H-NMR (400 MHz, DMSO-d₆, ppm): δ 8.16 (s, 2H), 7.92 (s, 1H), 7.78(d, J = 2.4 Hz, 1H), 7.26-7.22 (m, 3H), 7.17-7.15 (m, 1H), 7.13- 7.08(m, 2H), 4.28 (q, J = 7.2 Hz, 2H), 3.59 (d, J = 12.4 Hz, 2H), 2.73 (t, J= 11.7 Hz, 2H), 2.64 (tt, J = 15.3, 6.1 Hz, 2H), 2.54 (dd, J = 25.6,13.4 Hz, 1H), 2.42-2.32 (m, 2H), 1.94 (ddd, J = 23.8, 13.4, 7.4 Hz, 1H),1.85- 1.73 (m, 1H), 1.64 (d, J = 10.8 Hz, 2H), 1.38- 1.22 (m, 5H). 127

518.1 H-NMR (400 MHz, DMSO-d6, ppm): δ 12.38 (brs, 1H), 8.03 (d, J = 8.8Hz, 2H), 7.80 (d, J = 2.0 Hz, 1H), 7.61(s, 1H), 7.16-7.11 (m, 3H),7.04-6.99 (m, 2H), 4.41 (s, 2H), 4.24 (q, J = 7.2 Hz, 2H), 2.65-2.59 (m,2H), 2.38-2.31 (m, 2H), 2.15-2.08 (m, 2H), 1.89-1.85 (m, 1H), 1.82-1.75(m, 1H), 1.73-1. 69 (m, 2H), 1.51-1. 47 (m, 2H), 1.39-1.33 (m, 2H),1.28- 1.24 (t, J = 7.2 Hz, 3H), 1.20 (s, 1H). 128

430.1 H-NMR (400 MHz, DMSO-d6, ppm): δ 12.40 (brs, 1H), 7.85 (d, J = 2.0Hz, 1H), 7.59 (s, 1H), 7.22-7.17 (m, 3H), 6.80-6.78 (m, 2H), 3.70 (dd, J= 7.3, 4.1 Hz, 1H), 3.56 (dd, J = 11.1, 4.4 Hz, 1H), 3.58-3.30 (m, 2H),3.27- 3.21 (m, 2H), 3.11-3.09 (m, 1H), 2.62 (ddd, J = 11.8, 8.8, 5.5 Hz,2H), 2.47-2.30 (m, 2H), 2.07-2.05 (m, 1H), 1.89-1.71 (m, 2H), 0.72 (d, J= 6.8 Hz, 3H), 0.59 (d, J = 6.8 Hz, 3H).

The compounds described herein can be prepared from readily availablestarting materials using methods known in the art. It will beappreciated that where typical or preferred process conditions (i.e.,reaction temperatures, times, mole ratios of reactants, solvents, andpressures, etc.) are given, other process conditions can also be usedunless otherwise stated. Optimum reaction conditions may vary with theparticular reactants or solvents used, but such conditions can bedetermined by those skilled in the art by routine optimizationprocedures. The chemicals used in the above-described synthetic routesmay include, for example, solvents, reagents, catalysts, and protectinggroup and deprotecting group reagents. The methods described above mayalso additionally include steps, either before or after the stepsdescribed specifically herein, to add or remove suitable protectinggroups in order to ultimately allow synthesis of the compounds. Inaddition, various synthetic steps may be performed in an alternatesequence or order to give the desired compounds. Synthetic chemistrytransformations and protecting group methodologies (protection anddeprotection) useful in synthesizing applicable compounds are known inthe art and include, for example, those described in R. Larock,Comprehensive Organic Transformations, VCH Publishers (1989); T. W.Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3^(rd)Ed., John Wiley and Sons (1999); L. Fieser and M. Fieser, Fieser andFieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); andL. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, JohnWiley and Sons (1995) and subsequent editions thereof.

The compounds of Formula (I) provided herein can be prepared fromreadily available starting materials using the following general methodsand procedures. Exemplary schematic illustrations for synthesizing thecompounds of the invention described herein are provided below. Wheretypical or preferred process conditions (i.e., reaction temperatures,times, mole ratios of reactants, solvents, pressures, etc.) are given,other process conditions can also be used unless otherwise stated.Optimum reaction conditions may vary with the particular reactants orsolvents used, but such conditions can be determined by those skilled inthe art by routine optimization procedures.

The compounds of the invention may be prepared according to the generalScheme A. Compounds A1, where G=halogen are commercially available orcan be assembled via standard transformations known to those of ordinaryproficiency in the art of organic/medicinal chemistry. Compounds A2 canbe prepared from A1 by base or palladium promoted displacement of thehalogen by amines HNR⁴R⁵ in a solvent such as THF, DMF, NMP or the like.Reduction of the nitro group can be done under reductive conditions suchas but not limited to palladium on charcoal under an atmosphere ofhydrogen and in a solvent such as methanol or ethyl acetate to affordintermediates A3. Treatment of anilines A3 with an isocyanate A4, in asolvent such as THF at a temperature between ambient and the boilingpoint of the solvent, to afford intermediate A5. Nitriles A5 could behydrolyzed under either acidic or alkaline conditions to make I-a. Onthe other hand, nitriles A5 could be converted into tetrazoles I-b byheating with an azide such as NaN₃, TMSN₃ or tributyltinazide in asolvent such as toluene at or near the boiling point.

Scheme A. Preparation of Compounds of Formula (I)

Scheme B. Preparation of Acid Derivatives I-a.

Scheme B illustrates an alternative way to convert intermediates A3 toacid derivatives I-a. Nitriles A3 could be hydrolyzed under eitheracidic or alkaline conditions to make B1. Treatment of anilines B1 withan isocyanate A4, in a solvent such as THF at a temperature betweenambient and the boiling point of the solvent, to afford I-a.

Scheme C. Preparation of Compounds of Formula (I)

The compounds of the invention may also be prepared according to thegeneral Scheme C. Compounds C1, where G=halogen are commerciallyavailable or can be assembled via standard transformations known tothose of ordinary proficiency in the art of organic/medicinal chemistry.Compounds C2 can be prepared from C1 by base or palladium promoteddisplacement of the halogen by amines HNR⁴R⁵ in a solvent such as THF,DMF, NMP or the like. Reduction of the nitro group can be done underreductive conditions such as but not limited to palladium on charcoalunder an atmosphere of hydrogen and in a solvent such as methanol orethyl acetate to afford intermediates C3. Treatment of anilines C3 withan isocyanate A4, in a solvent such as THF at a temperature betweenambient and the boiling point of the solvent, to afford intermediate C4.The saponification of C4 to I-a could be generally accomplished by theuse of an alkali metal hydroxide in aqueous or mixed aqueous/organicsolvents.

Scheme D. Preparation of Compounds of Formula (I)

The compounds of the invention may also be prepared according to thegeneral Scheme D. Compounds D1, where G=halogen are commerciallyavailable or can be assembled via standard transformations known tothose of ordinary proficiency in the art of organic/medicinal chemistry.Compounds D2 can be prepared from D1 by base or palladium promoteddisplacement of the halogen by amines HNR⁴R⁵ in a solvent such as THF,DMF, NMP or the like. Palladium promoted cross-coupling could generatethiol ether D3. Reduction of the nitro group can be done under reductiveconditions such as but not limited to palladium on charcoal under anatmosphere of hydrogen and in a solvent such as methanol or ethylacetate to afford intermediates D4. Treatment of anilines D4 with anisocyanate A4, in a solvent such as THF at a temperature between ambientand the boiling point of the solvent, to afford intermediate D5.De-protection of thiol ether D5 could provide thiol D6, which may beconverted to ester derivatives D7 under displacement conditions. Thesaponification of D7 to IV-a could be generally accomplished by the useof an alkali metal hydroxide in aqueous or mixed aqueous/organicsolvents.

Scheme E. Preparation of Compounds of Formula (I)

Referring to Scheme E, compounds E1 where V is CN or ester can beprepared using the transformation described above. Anilines E1 may beconverted to isothiocyanates by treating with reagents such as thionylchloride. Treated the isothiocyanates with o-dimines, following byheating the reaction in the presence of base, could form benzimidazolesE3. The saponification of E3 to V-a could be generally accomplished bythe use of an alkali metal hydroxide in aqueous or mixed aqueous/organicsolvents.

Scheme F. Preparation of Compounds of Formula (I)

In Scheme F, compounds F1 can be prepared from amine E1 by base orpalladium promoted displacement of the halogen of X—R¹⁸. Thesaponification of F1 to V-b could be generally accomplished by the useof an alkali metal hydroxide in aqueous or mixed aqueous/organicsolvents.

Scheme G. Preparation of Compounds of Formula (I)

In Scheme G, compounds F1 can be prepared from amine E1 by amideformation such as treating with acyl chloride in the presence of base.The saponification of G1 to V-c could be generally accomplished by theuse of an alkali metal hydroxide in aqueous or mixed aqueous/organicsolvents.

Pharmaceutical Compositions and Kits

The present disclosure provides pharmaceutical compositions comprising acompound described herein, or a pharmaceutically acceptable saltthereof, and optionally a pharmaceutically acceptable excipient. Incertain embodiments, a pharmaceutical composition described hereincomprises a compound described herein, or a pharmaceutically acceptablesalt thereof, and a pharmaceutically acceptable excipient. Thepharmaceutical compositions described herein are useful in treatingand/or preventing proliferative diseases (e.g., cancer) and infectiousdiseases (e.g., viral or bacterial infectious diseases). In someexamples, the pharmaceutical compositions described herein may furthercomprise a second therapeutic agent, such as those described herein,e.g., an anti-cancer agent or an antiviral agent.

In certain embodiments, the cell contacted with an effective amount of acompound or pharmaceutical composition described herein is in vitro. Incertain embodiments, the contacted cell is ex vivo. In certainembodiments, the cell described herein is in vivo. In certainembodiments, the cell described herein is a malignant cell (e.g.,malignant blood cell).

In certain embodiments, the compound described herein is provided in aneffective amount in the pharmaceutical composition. In certainembodiments, the effective amount is a therapeutically effective amount(e.g., amount effective for treating a proliferative disease in asubject in need thereof). In certain embodiments, the proliferativedisease is cancer. In certain embodiments, the proliferative disease iscancer, e.g., non-small cell lung cancer, small cell lung cancer, breastcancer, renal cell carcinoma, bladder cancer, head and neck cancer,ovarian cancer, brain cancer, cancers of the gastrointestinal tract,liver cancer, pancreatic cancer, melanoma, leukemia, lymphoma, etc. Incertain embodiments, the effective amount is a prophylacticallyeffective amount (e.g., amount effective for preventing a proliferativedisease in a subject in need thereof and/or for keeping a subject inneed thereof in remission of a proliferative disease).

Pharmaceutical compositions described herein can be prepared by anymethod known in the pharmaceutical industry. In general, suchpreparatory methods include bringing the compound described herein(i.e., the “active ingredient”) into association with a carrier orexcipient, and/or one or more other accessory ingredients, and then, ifnecessary and/or desirable, shaping, and/or packaging the product into adesired single- or multi-dose unit.

Pharmaceutical compositions can be prepared, packaged, and/or sold inbulk, as a single unit dose, and/or as a plurality of single unit doses.A “unit dose” is a discrete amount of the pharmaceutical compositioncomprising a predetermined amount of the active ingredient. The amountof the active ingredient is generally equal to the dosage of the activeingredient which would be administered to a subject and/or a convenientfraction of such a dosage, such as one-half or one-third of such adosage.

Relative amounts of the active ingredient, the pharmaceuticallyacceptable excipient, and/or any additional ingredients in apharmaceutical composition described herein will vary, depending uponthe identity, size, and/or condition of the subject treated and furtherdepending upon the route by which the composition is to be administered.The composition may comprise between 0.1% and 100% (w/w) activeingredient.

Pharmaceutically acceptable excipients used in the manufacture ofprovided pharmaceutical compositions include inert diluents, dispersingand/or granulating agents, surface active agents and/or emulsifiers,disintegrating agents, binding agents, preservatives, buffering agents,lubricating agents, and/or oils. Excipients such as cocoa butter andsuppository waxes, coloring agents, coating agents, sweetening,flavoring, and perfuming agents may also be present in the composition.

Liquid dosage forms for oral and parenteral administration includepharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active ingredients,the liquid dosage forms may comprise inert diluents commonly used in theart such as, for example, water or other solvents, solubilizing agentsand emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed,groundnut, corn, germ, olive, castor, and sesame oils), glycerol,tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid estersof sorbitan, and mixtures thereof. Besides inert diluents, the oralcompositions can include adjuvants such as wetting agents, emulsifyingand suspending agents, sweetening, flavoring, and perfuming agents. Incertain embodiments for parenteral administration, the conjugatesdescribed herein are mixed with solubilizing agents such as Cremophor®,alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins,polymers, and mixtures thereof.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions can be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation can be a sterile injectable solution,suspension, or emulsion in a nontoxic parenterally acceptable diluent orsolvent, for example, as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that can be employed are water,Ringer's solution, U.S.P., and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or di-glycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activeingredient is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or (a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, (b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, (c) humectants such as glycerol, (d) disintegratingagents such as agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, (e) solutionretarding agents such as paraffin, (f) absorption accelerators such asquaternary ammonium compounds, (g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, (h) absorbents such as kaolinand bentonite clay, and (i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets, and pills, thedosage form may include a buffering agent.

Solid compositions of a similar type can be employed as fillers in softand hard-filled gelatin capsules using such excipients as lactose ormilk sugar as well as high molecular weight polyethylene glycols and thelike. The solid dosage forms of tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the art of pharmacology. Theymay optionally comprise opacifying agents and can be of a compositionthat they release the active ingredient(s) only, or preferentially, in acertain part of the intestinal tract, optionally, in a delayed manner.Examples of encapsulating compositions which can be used includepolymeric substances and waxes. Solid compositions of a similar type canbe employed as fillers in soft and hard-filled gelatin capsules usingsuch excipients as lactose or milk sugar as well as high molecularweight polethylene glycols and the like.

The active ingredient can be in a micro-encapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings, and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active ingredient can be admixed with at least oneinert diluent such as sucrose, lactose, or starch. Such dosage forms maycomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may comprise bufferingagents. They may optionally comprise opacifying agents and can be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of encapsulating agents which can be usedinclude polymeric substances and waxes.

Suitable devices for use in delivering intradermal pharmaceuticalcompositions described herein include short needle devices. Intradermalcompositions can be administered by devices which limit the effectivepenetration length of a needle into the skin. Alternatively oradditionally, conventional syringes can be used in the classical mantouxmethod of intradermal administration. Jet injection devices whichdeliver liquid formulations to the dermis via a liquid jet injectorand/or via a needle which pierces the stratum corneum and produces a jetwhich reaches the dermis are suitable. Ballistic powder/particledelivery devices which use compressed gas to accelerate the compound inpowder form through the outer layers of the skin to the dermis aresuitable.

Although the descriptions of pharmaceutical compositions provided hereinare principally directed to pharmaceutical compositions which aresuitable for administration to humans, such compositions are generallysuitable for administration to animals of all sorts. Modification ofpharmaceutical compositions suitable for administration to humans inorder to render the compositions suitable for administration to variousanimals is well understood, and the ordinarily skilled veterinarypharmacologist can design and/or perform such modification with ordinaryexperimentation.

The compounds provided herein are typically formulated in dosage unitform for ease of administration and uniformity of dosage. It will beunderstood, however, that the total daily usage of the compositionsdescribed herein will be decided by a physician within the scope ofsound medical judgment. The specific therapeutically effective doselevel for any particular subject or organism will depend upon a varietyof factors including the disease being treated and the severity of thedisorder; the activity of the specific active ingredient employed; thespecific composition employed; the age, body weight, general health,sex, and diet of the subject; the time of administration, route ofadministration, and rate of excretion of the specific active ingredientemployed; the duration of the treatment; drugs used in combination orcoincidental with the specific active ingredient employed; and likefactors well known in the medical arts.

Also encompassed by the disclosure are kits (e.g., pharmaceuticalpacks). The kits provided may comprise a pharmaceutical composition orcompound described herein and a container (e.g., a vial, ampule, bottle,syringe, and/or dispenser package, or other suitable container). In someembodiments, provided kits may optionally further include a secondcontainer comprising a pharmaceutical excipient for dilution orsuspension of a pharmaceutical composition or compound described herein.In some embodiments, the pharmaceutical composition or compounddescribed herein provided in the first container and the secondcontainer are combined to form one unit dosage form.

In certain embodiments, a kit described herein includes a firstcontainer comprising a compound or pharmaceutical composition describedherein. In certain embodiments, a kit described herein is useful intreating a proliferative disease (e.g., non-small cell lung cancer smallcell lung cancer, breast cancer, renal cell carcinoma, bladder cancer,head and neck cancer, ovarian cancer, brain cancer, cancers of thegastrointestinal tract, liver cancer, pancreatic cancer, melanoma,leukemia, lymphoma, etc.) in a subject in need thereof, and/orpreventing a proliferative disease in a subject in need thereof.

In certain embodiments, a kit described herein further includesinstructions for using the compound or pharmaceutical compositionincluded in the kit. A kit described herein may also include informationas required by a regulatory agency such as the U.S. Food and DrugAdministration (FDA). In certain embodiments, the information includedin the kits is prescribing information. In certain embodiments, the kitsand instructions provide for treating a proliferative disease in asubject in need thereof, and/or preventing a proliferative disease in asubject in need thereof. A kit described herein may include one or moreadditional pharmaceutical agents described herein as a separatecomposition.

Methods of Treatment

As shown in the Examples below, exemplary IDO inhibiting compoundsdescribed herein successfully demonstrated in vitro potency and in vivoefficacy. The compounds described herein are useful in treating and/orpreventing proliferative diseases (e.g., cancer) via the inhibition ofIDO and inhibition of tryptophan catabolism resulting in reduction ofthe kynurenine level. Moreover, these compounds showed lower humanhepatic clearance compared to other IDO inhibitors known in the art,including INCB-24360 and others disclosed in WO2014150677 andWO2014150646. Accordingly, the present disclosure provides methods fortreating diseases associated with IDO with one or more of the IDOinhibiting compounds described herein. Diseases associated with IDOinclude, but are not limited to, cancer, infectious diseases, andAlzhimer's disease. In certain embodiments, the infectious disease is aviral infection.

Accordingly, the present disclosure provides methods of treating aproliferative disease in a subject in need thereof, the methodscomprising administering to the subject an effective amount (e.g.,therapeutically effective amount) of a compound, or pharmaceuticalcomposition thereof, described herein.

Another aspect of the present disclosure relates to methods ofpreventing proliferative disease in a subject in need thereof, themethods comprising administering to the subject an effective amount(e.g., prophylactically effective amount) of a compound, orpharmaceutical composition thereof, described herein.

The compounds and pharmaceutical compositions described herein areuseful in treating and/or preventing proliferative diseases. In certainembodiments, the proliferative disease is cancer (e.g., cancer(non-small cell lung cancer, small cell lung cancer), breast cancer,prostate cancer, ovarian cancer, endometrial cancer, cervical cancer,bladder cancer, head and neck cancer, renal cell carcinoma, esophagealcancer, pancreatic cancer, brain cancer, cancers of the gastrointestinaltract, liver cancer, leukemia, lymphoma, melanoma, multiple myeloma,Ewing's sarcoma, or osteosarcoma). In certain embodiments, theproliferative disease is an inflammatory disease. In certainembodiments, the proliferative disease is an immune-related disease.

In certain embodiments, the method described herein further includesadministering to the subject an additional pharmaceutical agent. Incertain embodiments, the method described herein further includescontacting the biological sample with an additional pharmaceuticalagent. In certain embodiments, the method described herein furtherincludes contacting the tissue with an additional pharmaceutical agent.In certain embodiments, the method described herein further includestreating the subject in need of the treatment a second anti-cancertherapy, such as chemotherapy, immunotherapy (e.g., anti-PD-1 oranti-PD-L1 antibody), cell therapy (e.g., CAR-T cell therapy), surgery,and/or transplantation (e.g., bone marrow transplantation). In someexamples, the second anti-cancer therapy involves the use of one or moreanti-cancer agents, e.g., those known in the art, including anti-cancerdrugs in clinical use or in clinical trials.

The compounds and compositions provided herein can be administered byany route, including enteral (e.g., oral), parenteral, and/orintravenous. Specifically contemplated routes are oral administration,intravenous administration (e.g., systemic intravenous injection),regional administration via blood and/or lymph supply, and/or directadministration to an affected site. In general, the most appropriateroute of administration will depend upon a variety of factors includingthe nature of the agent (e.g., its stability in the environment of thegastrointestinal tract), and/or the condition of the subject (e.g.,whether the subject is able to tolerate oral administration).

The exact amount of a compound required to achieve an effective amountwill vary from subject to subject, depending, for example, on species,age, and general condition of a subject, severity of the side effects ordisorder, identity of the particular compound, mode of administration,and the like. An effective amount may be included in a single dose(e.g., single oral dose) or multiple doses (e.g., multiple oral doses).In certain embodiments, when multiple doses are administered to asubject or applied to a biological sample, tissue, or cell, any twodoses of the multiple doses include different or substantially the sameamounts of a compound described herein. In certain embodiments, whenmultiple doses are administered to a subject or applied to a biologicalsample, tissue, or cell, the frequency of administering the multipledoses to the subject or applying the multiple doses to the tissue orcell is two doses a day, one dose a day, one dose every other day, onedose every third day, one dose every week, one dose every two weeks, onedose every three weeks, or one dose every four weeks. In certainembodiments, the frequency of administering the multiple doses to thesubject or applying the multiple doses to the tissue or cell is one doseper day. In certain embodiments, the frequency of administering themultiple doses to the subject or applying the multiple doses to thetissue or cell is two doses per day. In certain embodiments, thefrequency of administering the multiple doses to the subject or applyingthe multiple doses to the tissue or cell is three doses per day. Incertain embodiments, when multiple doses are administered to a subjector applied to a biological sample, tissue, or cell, the duration betweenthe first dose and last dose of the multiple doses is half a day, oneday, two days, four days, one week, two weeks, three weeks, one month,two months, three months, four months, six months, nine months, oneyear, two years, three years, four years, five years, seven years, tenyears, fifteen years, twenty years, or the lifetime of the subject,biological sample, tissue, or cell. In certain embodiments, the durationbetween the first dose and last dose of the multiple doses is threemonths, six months, or one year. In certain embodiments, the durationbetween the first dose and last dose of the multiple doses is thelifetime of the subject, biological sample, tissue, or cell. In certainembodiments, a dose (e.g., a single dose, or any dose of multiple doses)described herein includes independently between 0.1 μg and 1 μg, between0.001 mg and 0.01 mg, between 0.01 mg and 0.1 mg, between 0.1 mg and 1mg, between 1 mg and 3 mg, between 3 mg and 10 mg, between 10 mg and 30mg, between 30 mg and 100 mg, between 100 mg and 300 mg, between 300 mgand 1,000 mg, or between 1 g and 10 g, inclusive, of a compounddescribed herein. In certain embodiments, a dose described hereinincludes independently between 3 mg and 10 mg, inclusive, of a compounddescribed herein. In certain embodiments, a dose described hereinincludes independently between 10 mg and 30 mg, inclusive, of a compounddescribed herein. In certain embodiments, a dose described hereinincludes independently between 30 mg and 100 mg, inclusive, of acompound described herein. In certain embodiments, a dose describedherein includes independently between 100 mg and 300 mg, inclusive, of acompound described herein. In certain embodiments, a dose describedherein includes independently between 300 mg and 1000 mg, inclusive, ofa compound described herein.

Dose ranges as described herein provide guidance for the administrationof provided pharmaceutical compositions to an adult. The amount to beadministered to, for example, a child or an adolescent can be determinedby a medical practitioner or person skilled in the art and can be loweror the same as that administered to an adult.

A compound or composition, as described herein, can be administered incombination with one or more additional pharmaceutical agents (e.g.,therapeutically and/or prophylactically active agents) useful intreating and/or preventing a proliferative disease. The compounds orcompositions can be administered in combination with additionalpharmaceutical agents that improve their activity (e.g., activity (e.g.,potency and/or efficacy) in treating a proliferative disease in asubject in need thereof, and/or in preventing a proliferative disease ina subject in need thereof), improve bioavailability, improve safety,reduce drug resistance, reduce and/or modify metabolism, inhibitexcretion, and/or modify distribution in a subject, biological sample,tissue, or cell. It will also be appreciated that the therapy employedmay achieve a desired effect for the same disorder, and/or it mayachieve different effects. In certain embodiments, a pharmaceuticalcomposition described herein including a compound described herein andan additional pharmaceutical agent shows a synergistic effect that isabsent in a pharmaceutical composition including one of the compound andthe additional pharmaceutical agent, but not both.

The compound or composition can be administered concurrently with, priorto, or subsequent to one or more additional pharmaceutical agents, whichmay be useful as, e.g., combination therapies in treating and/orpreventing a proliferative disease. Pharmaceutical agents includetherapeutically active agents. Pharmaceutical agents also includeprophylactically active agents. Pharmaceutical agents include smallorganic molecules such as drug compounds (e.g., compounds approved forhuman or veterinary use by the U.S. Food and Drug Administration asprovided in the Code of Federal Regulations (CFR)), peptides, proteins,carbohydrates, monosaccharides, oligosaccharides, polysaccharides,nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides orproteins, small molecules linked to proteins, glycoproteins, steroids,nucleic acids, DNAs, RNAs, nucleotides, nucleosides, oligonucleotides,antisense oligonucleotides, lipids, hormones, vitamins, and cells. Incertain embodiments, the additional pharmaceutical agent is apharmaceutical agent useful in treating a proliferative disease. Incertain embodiments, the additional pharmaceutical agent is apharmaceutical agent useful in preventing a proliferative disease. Incertain embodiments, the additional pharmaceutical agent is apharmaceutical agent approved by a regulatory agency (e.g., the US FDA)for treating and/or preventing a proliferative disease. Each additionalpharmaceutical agent may be administered at a dose and/or on a timeschedule determined for that pharmaceutical agent. The additionalpharmaceutical agents may also be administered together with each otherand/or with the compound or composition described herein in a singledose or administered separately in different doses. The particularcombination to employ in a regimen will take into account compatibilityof the compound described herein with the additional pharmaceuticalagent(s) and/or the desired therapeutic and/or prophylactic effect to beachieved. In general, it is expected that the additional pharmaceuticalagent(s) in combination be utilized at levels that do not exceed thelevels at which they are utilized individually. In some embodiments, thelevels utilized in combination will be lower than those utilizedindividually.

In certain embodiments, the additional pharmaceutical agent is ananti-proliferative agent (e.g., anti-cancer agent). In certainembodiments, the additional pharmaceutical agent is an anti-canceragent, anti-angiogenesis agent, anti-inflammatory agent,immunosuppressant, anti-bacterial agent, anti-viral agent,cardiovascular agent, cholesterol-lowering agent, anti-diabetic agent,anti-allergic agent, pain-relieving agent, or a combination thereof. Incertain embodiments, the compounds described herein or pharmaceuticalcompositions can be administered in combination with an anti-cancertherapy including, but not limited to, transplantation (e.g., bonemarrow transplantation, stem cell transplantation), surgery, radiationtherapy, cell therapy (e.g., CAR-T cell therapy), immunotherapy (e.g.,anti-PD-1 or anti-PD-L1 antibody, or a cancer vaccine), andchemotherapy. Treatment with the IDO inhibiting compound may beperformed prior to, concurrently with, or after the other therapy.

When any of the IDO inhibiting compounds described herein is used fortreating a viral infection, it may be co-used with a second anti-viralagent, which may be different from any of the IDO inhibiting compoundsdescribed herein. In some examples, the anti-viral agent is ananti-viral vaccine. The second anti-viral agent may be administeredprior to, concurrently, or after the administration of the IDOinhibiting compound.

Other combined therapies involving IDO inhibitors, as known in the art,are also within the scope of the present disclosure. See, for example,WO2015006520, the relevant disclosures of which are incorporated byreference for the purposes or subject matter referenced herein.

Without further elaboration, it is believed that one skilled in the artcan, based on the above description, utilize the present invention toits fullest extent. The following specific embodiments are, therefore,to be construed as merely illustrative, and not limitative of theremainder of the disclosure in any way whatsoever. All publicationscited herein are incorporated by reference for the purposes or subjectmatter referenced herein.

EXAMPLES

In order that the present disclosure may be more fully understood, thefollowing examples are set forth. The synthetic and biological examplesdescribed in this application are offered to illustrate the compounds,pharmaceutical compositions, and methods provided herein and are not tobe construed in any way as limiting their scope.

Example 1

Step 1. Synthesis of 1-1

Into a 100-mL 3-necked round-bottom flask, was placed a solution of2-(4-fluorophenyl)acetonitrile (5 g, 37.00 mmol) in sulfuric acid (50mL). This was followed by addition of potassium nitrate (5.6 g), inportions at 0° C. in 10 min. The resulting solution was stirredovernight at room temperature. The reaction mixture was poured into 150mL of water/ice. The resulting solution was extracted with 3×100 mL ofethyl acetate. The combined organic layer was washed with 3×100 mL ofbrine, dried over anhydrous sodium sulfate and concentrated under vacuumto give 2-(4-fluoro-3-nitrophenyl)acetamide (6 g, 82% yield).

Step 2. Synthesis of 1-2

Into a 250-mL 3-necked round-bottom flask, was placed a solution of2-(4-fluoro-3-nitrophenyl)acetamide (6 g, 30.28 mmol) in DMSO (60 mL),bis(2-methylpropyl)amine (5.86 g, 45.34 mmol), and DIEA (7.81 g, 60.66mmol). The resulting solution was heated to 100° C. and stirred at thesame temperature for overnight. The reaction mixture was cooled to roomtemperature, and then quenched by addition of 50 mL of water. Theresulting solution was extracted with 3×100 mL of ethyl acetate. Thecombined organic layer was washed with 3×100 mL of brine, dried overanhydrous sodium sulfate and concentrated under vacuum. The residue wasapplied onto a silica gel column with ethyl acetate/petroleum ether(1:10˜1:3) to afford2-[4-[bis(2-methylpropyl)amino]-3-nitrophenyl]acetamide (7 g, 75%yield).

Step 3. Synthesis of 1-3

Into a 250-mL 3-necked round-bottom flask, was placed a solution of2-[4-[bis(2-methylpropyl)amino]-3-nitrophenyl]acetamide (7 g, 22.77mmol) in dioxane (70 mL), TFAA (7 mL), and triethylamine (3 mL). Theresulting solution was heated to 100° C. and stirred at the sametemperature overnight. The reaction mixture was cooled to roomtemperature. The reaction was then quenched by addition of 50 mL ofwater. The resulting solution was extracted with 3×100 mL of ethylacetate. The combined organic layer was washed with 3×100 mL of brine,dried over anhydrous sodium sulfate and concentrated under vacuum. Theresidue was applied onto a silica gel column with ethylacetate/petroleum ether (1:20˜1:3) to afford2-[4-[bis(2-methylpropyl)amino]-3-nitrophenyl]acetonitrile (6.1 g, 93%yield).

Step 4. Synthesis of 1-4

Into a 100-mL round-bottom flask, was placed a solution of2-[4-[bis(2-methylpropyl)amino]-3-nitrophenyl]acetonitrile (3 g, 10.37mmol) in ethanol/H₂O (30/10 mL), Fe (3.49 g), and NH₄Cl (380 mg, 7.10mmol). The resulting solution was stirred for 2 h at 80° C. The reactionmixture was cooled to room temperature. The resulting mixture wasconcentrated under vacuum. The resulting solution was extracted with3×50 mL of ethyl acetate. The combined organic layers was washed with3×50 mL of brine, dried over anhydrous sodium sulfate and concentratedunder vacuum. The residue was applied onto a silica gel column withethyl acetate/petroleum ether (1:10-1:1) to afford2-[3-amino-4-[bis(2-methylpropyl)amino]phenyl]acetonitrile (1.1 g, 41%yield).

Step 5. Synthesis of 1-5

Into a 100-mL 3-necked round-bottom flask, was placed a solution of2-[3-amino-4-[bis(2-methylpropyl)amino]phenyl]acetonitrile (1.1 g, 4.24mmol) in tetrahydrofuran (50 mL), 2,4-difluoro-1-isocyanatobenzene (790mg, 5.09 mmol), and triethylamine (860 mg, 8.50 mmol). The resultingsolution was stirred for 3 h at room temperature. The resulting mixturewas concentrated under vacuum. The residue was applied onto a silica gelcolumn with ethyl acetate/petroleum ether (1:10˜1:3) to afford3-[2-[bis(2-methylpropyl)amino]-5-(cyanomethyl)phenyl]-1-(2,4-difluorophenyl)urea(700 mg, 40% yield).

Step 6. Synthesis of 1

Into a 8-mL sealed tube, was placed a solution of1-[2-[bis(2-methylpropyl)amino]-5-(cyanomethyl)phenyl]-3-(2,4-difluorophenyl)urea(300 mg, 0.72 mmol) in ethanol/H₂O (5/1 mL), and sodium hydroxide (15%aq.) (1 mL). The resulting solution was stirred at 60° C. for overnight.The reaction mixture was cooled to room temperature and concentratedunder vacuum. The pH value of the solution was adjusted to 6 withhydrogen chloride (1 N). The resulting mixture was concentrated undervacuum. The crude product was purified by Prep-HPLC with the followingconditions: Column, Waters X-bridge RP18, 19*150 mm, 5 um; mobile phase,ACN/water (0.05% NH₃H₂O) from 20% to 38% within 5.6 min, flow rate: 20mL/min; Detector, 254 nm. This resulted in 72.2 mg (23% yield) of2-[4-[bis(2-methylpropyl)amino]-3-[[(2,4-difluorophenyl)carbamoyl]amino]phenyl]aceticacid as off-white solid. LCMS (ES, m/z): 434 [M+H]⁺. HNMR (300 MHz,DMSO-d₆, ppm): δ 9.27 (s, 1H), 8.06 (s, 1H), 7.96-7.88 (m, 1H), 7.78 (d,J=1.8 Hz, 1H), 7.33-7.25 (m, 1H), 7.12 (d, J=8.1 Hz, 1H), 7.07-7.00 (m,1H), 6.86 (dd, J=8.4, 2.1 Hz, 1H), 3.38 (s, 2H), 2.66 (d, J=6.9 Hz, 4H),1.69-1.61 (m, 2H), 0.84 (d, J=6.6 Hz, 12H).

Example 2

Step 1. Synthesis of 2-1

To a solution of2-[4-[bis(2-methylpropyl)amino]-3-nitrophenyl]acetonitrile (2 g, 6.91mmol) in tetrahydrofuran (20 mL) at 0° C., was added sodium hydride (250mg, 6.25 mmol) portionwise. After stirring at room temperature for 1 h,the reaction was cooled to 0° C., and iodomethane (1.18 g, 8.31 mmol)was added dropwise. The reaction mixture was then stirred at roomtemperature for another 2 h before quenched by the addition of saturatedammonium chloride solution (20 mL). The mixture was extracted with ethylacetate (50 mL×3), and washed with brine (50 mL×3). The organic phasewas dried over anhydrous sodium sulfate and concentrated under vacuum.The residue was purified by Flash-Prep-HPLC [Column: C18; Mobile phaseA: Water (0.05% ammonium hydrogen carbonate), mobile phase B:acetonitrile; Gradient: 35% acetonitrile to 78% acetonitrile in 30 min]to afford the desired product (660 mg, 31% yield).

Step 2. Synthesis of 2-2

To a solution of2-[4-[bis(2-methylpropyl)amino]-3-nitrophenyl]propanenitrile (600 mg,1.98 mmol) in ethanol (20 mL), was added palladium on carbon (300 mg).The reaction was stirred for 2 h under H₂ balloon at room temperature.The solids were filtered out, and the filtrate was concentrated undervacuum to afford the desired product (530 mg, 72% yield).

Step 3. Synthesis of 2-3

To a solution of2-[3-amino-4-[bis(2-methylpropyl)amino]phenyl]propanenitrile (546 mg,2.00 mmol) in tetrahydrofuran (20 mL), were added triethylamine (610 mg,6.03 mmol) and 2,4-difluoro-1-isocyanatobenzene (456 mg, 2.94 mmol).After stirring at room temperature for 3 h, the reaction wasconcentrated under vacuum and the residue was purified byFlash-Prep-HPLC [Column: C18; Mobile phase A: Water (0.05% ammoniumhydrogen carbonate), mobile phase B: acetonitrile; Gradient: 45%acetonitrile to 85% acetonitrile in 30 min] to afford the desiredproduct (450 mg, 40% yield).

Step 4. Synthesis of 2

To a solution of3-[2-[bis(2-methylpropyl)amino]-5-(1-cyanoethyl)phenyl]-1-(2,4-difluorophenyl)urea(60 mg, 0.14 mmol) in ethanol (4 mL) and water (1 mL), was added sodiumhydroxide (400 mg, 10.00 mmol). After stirring at 60° C. for 16 h, thereaction mixture was cooled to room temperature and concentrated undervacuum. The residue was dissolved in water (10 mL), and hydrogenchloride (4 N) was employed to adjust the pH to 4. The mixture was thenextracted with ethyl acetate (20 mL×3). The organic phase was washedwith brine (20 mL×3), dried over anhydrous sodium sulfate andconcentrated under vacuum. The residue was purified by Prep-HPLC[Column: Waters X-bridge C18, 19×150 mm; Mobile phase A: water (0.05%trifluoroacetic acid), Mobile phase B: acetonitrile; Gradient: 25%acetonitrile to 60% acetonitrile; 8 min; Detector: 254 nm] to afford thedesired product (15.8 mg, 25% yield). LCMS (ES, m/z): 448.3 [M+H]⁺;¹HNMR: (300 MHz, DMSO-d₆, ppm): δ 9.29 (s, 1H), 8.06 (s, 1H), 7.93-7.91(m, 1H), 7.84 (d, J=1.8 Hz, 1H), 7.35-7.25 (m, 1H), 7.17-7.11 (m, 1H),7.06-6.97 (m, 1H), 6.91-6.88 (m, 1H), 3.58-3.51(m, 1H), 2.66 (d, J=6.9Hz, 4H), 1.69-1.61 (m, 2H), 1.32 (d, J=7.2 Hz, 3H), 0.84 (d, J=6.6 Hz,12H).

Example 3

Step 1. Synthesis of 3-1

To a solution of 2-(4-fluorophenyl)acetonitrile (11 g, 81.40 mmol) intetrahydrofuran (250 mL) at 0° C., was added sodium hydride (3.91 g,97.75 mmol). The reaction was then warmed to room temperature andstirred for 30 min. The reaction mixture was cooled to 0° C. again andbromoethane (9.76 g, 89.57 mmol) was added. The reaction was thenstirred at room temperature for overnight. Water (100 mL) was added andthe mixture was extracted with ethyl acetate (100 mL×2). The organiclayer was dried over anhydrous sodium sulfate and concentrated undervacuum. The residue was purified by silica gel column with ethylacetate/petroleum ether (1/10) as eluent to afford2-(4-fluorophenyl)butanenitrile (9 g, 83% yield).

Step 2. Synthesis of 3-2

To a solution of 2-(4-fluorophenyl)butanenitrile (9 g, 55.21 mmol) insulfuric acid (200 mL) at 0° C., was added potassium nitrate (8.28 g,82.82 mmol). The reaction was then stirred at 25° C. for 1 h. Thereaction was quenched by addition of water/ice (600 mL) and the mixturewas extracted with ethyl acetate (100 mL×3). The organic layer waswashed with saturated aqueous sodium bicarbonate (30 mL×2), dried overanhydrous sodium sulfate, and concentrated under vacuum. The residue waspurified by silica gel column chromatography with ethylacetate/petroleum ether (1/4) as eluent to afford2-(4-fluoro-3-nitrophenyl)butanenitrile (5 g, 44% yield).

Step 3. Synthesis of 3-3

To a solution of 2-(4-fluoro-3-nitrophenyl)butanenitrile (5 g, 24 mmol)and diisopropylethylamine (6.2 g, 48 mmol) in dimethylsulfoxide (100mL), was added bis(2-methylpropyl)amine (3.7 g, 28.8 mmol). The reactionwas then warmed to 100° C. and stirred for 1 h. After cooling down toroom temperature, ethyl acetate (200 mL) was added and the mixture waswashed with water (100 mL×2). The organic layer was dried over anhydroussodium sulfate and concentrated under vacuum. The residue was purifiedby silica gel column with ethyl acetate/petroleum ether (1/10) to afford2-[4-[bis(2-methylpropyl)amino]-3-nitrophenyl]butanenitrile (4 g, 53%yield).

Step 4. Synthesis of 3-4

A mixture of 2-[4-[bis(2-methylpropyl)amino]-3-nitrophenyl]butanenitrile(4 g, 12.60 mmol) and palladium on carbon (0.4 g) in methanol (20 mL)was stirred under hydrogen atmosphere (1 atm) at 25° C. for overnight.The reaction was filtered through Celite and the filtrate wasconcentrated under vacuum. The residue was purified by silica gel columnwith ethyl acetate/petroleum ether (1/10) to afford2-[3-amino-4-[bis(2-methylpropyl)amino]phenyl]butanenitrile (3 g, 83%yield).

Step 5. Synthesis of 3-5

A mixture of 2-[3-amino-4-[bis(2-methylpropyl)amino]phenyl]butanenitrile(1.16 g, 4.04 mmol) and potassium hydroxide (1.13 g, 20.14 mmol) inethanol (10 mL) and water (2 mL) was stirred in a sealed tube at 100° C.for 3 days. The pH value of the solution was adjusted to 7 with hydrogenchloride (2 N). Water (50 mL) was added and the mixture was extractedwith ethyl acetate (50 mL×3). The organic phase was dried over anhydroussodium sulfate and concentrated under vacuum to afford4-[3-amino-4-[bis(2-methylpropyl)amino]phenyl] oxane-4-carboxylic acid(1.16 g, 94% yield).

Step 6. Synthesis of 3-6

A mixture of 2-[3-amino-4-[bis(2-methylpropyl)amino]phenyl]butanoic acid(1.16 g, 3.79 mmol), 2,4-difluoro-1-isocyanatobenzene (707 mg, 4.56mmol), and triethylamine (768 mg, 7.59 mmol) in tetrahydrofuran (10 mL)was stirred at 25° C. for overnight. The mixture was concentrated andthe residue was purified by prep-HPLC to afford the desired product asracemic form. (Column: XBridge RP, 5 um, 19*150 mm; Mobile Phase A:NH₄HCO₃ 10 mmol/L in water; Mobile Phase B: ACN; Flow rate: 30 mL/min;Gradient: 45% B to 85% B in 8 min; Detector: 254 nm).

Step 7. Chiral Separation

The racemic product from step 6 was separated by chiral prep-HPLC withthe following conditions to afford examples 3A and 3B. (Column: IA, 20mmd*250 mmd; Mobile Phase: hexane with 3% alcohol; Flow rate: 15 mL/min;Detector: 254 nm.).

Example 3A: Retention time: 30.07 min. LRMS: (ES, m/z): 462.4 [M+H]⁺.¹HNMR: (300 MHz, DMSO-d₆): δ 12.22 (s, 1H), 9.30 (s, 1H), 8.07 (s, 1H),7.97-7.89 (m, 1H), 7.84 (s, 1H), 7.33-7.25 (m, 1H), 7.14 (d, J=8.4, 1H),7.06-6.99 (m, 1H), 6.88 (d, J=6.9 Hz, 1H), 3.30 (t, J=7.8, 1H), 2.65 (d,J=6.3, 4H), 1.97-1.85 (m, 1H), 1.70-1.55 (m, 3H), 0.83-0.78 (m, 15H).

Example 3B: Retention time: 38.62 min. LRMS (ES, m/z): 462.4 [M+H]⁺.¹HNMR: (300 MHz, DMSO-d₆): δ 12.20 (s, 1H), 9.30 (s, 1H), 8.07 (s, 1H),7.97-7.89 (m, 1H), 7.83 (s, 1H), 7.35-7.27 (m, 1H), 7.15 (d, J=8.4, 1H),7.07-7.01 (m, 1H), 6.90-6.87 (m, 1H), 3.33-3.27 (m, 1H), 2.66 (d, J=6.6,4H), 1.97-1.87 (m, 1H), 1.69-1.57 (m, 3H), 0.85-0.80 (m, 15H).

Example 4

Step 1. Synthesis of 4-1

To a solution of2-[4-[bis(2-methylpropyl)amino]-3-nitrophenyl]acetonitrile (0.7 g, 3.46mmol) in tetrahydrofuran (7 mL) at 0° C., was added sodium hydride (250mg, 10.37 mmol) portionwise. The mixture was then stirred at 0° C. for 1h, and iodomethane (0.858 g, 6.05 mmol) was added. After stirring atroom temperature for another 16 h, the reaction was quenched by additionof saturated ammonium chloride solution. The mixture was extracted withethyl acetate (50 mL×2), and washed with brine (50 mL×2). The combinedorganic phase was dried over anhydrous sodium sulfate and concentratedunder vacuum. The residue was purified by silica gel column with ethylacetate/petroleum ether (1/15) as the eluent to afford the desiredproduct (300 mg, 39% yield).

Followed the similar steps in example 2 to synthesize 4

Example 4: LRMS (ES, m/z): 462.40[M+H]⁺; ¹H-NMR: (300 MHz, DMSO-d₆,ppm): δ 12.05 (brs, 1H), 9.27 (s, 1H), 8.06 (s, 1H), 7.96-7.88 (m, 2H),7.33.7.26 (m, 1H), 7.15-7.12 (m, 1H), 7.07-6.94 (m, 2H), 2.65 (d, J=6.9Hz, 4H), 1.69-1.60 (m, 2H), 1.42 (s, 6H), 0.84 (d, J=6.6 Hz, 12H)

Example 5

Step 1. Synthesis of 5

To a solution of azidotrimethylsilane (185 mg, 1.61 mmol) in toluene (15mL), was added a solution of chlorodiethylalumane (194 mg, 1.61 mmol) intoluene (1.8 mL). After stirring at room temperature for 6 h, a solutionof3-[2-[bis(2-methylpropyl)amino]-5-(1-cyanoethyl)phenyl]-1-(2,4-difluorophenyl)urea(230 mg, 0.54 mmol) in toluene (20 mL) was added. The resulting mixturewas stirred at 110° C. for another 16 h. The reaction was cooled to roomtemperature and concentrated under vacuum. The residue was dissolved inethyl acetate (50 mL), and the mixture was washed with brine (30 mL×3).The organic phase was dried over anhydrous sodium sulfate andconcentrated under vacuum. The residue was purified by Prep-HPLC withthe following conditions [Column: Waters X-bridge C18, 19×150 nm; Mobilephase A: water (0.05% ammonia), Mobile phase B: acetonitrile; Gradient:25% acetonitrile to 52% acetonitrile; 6.8 min, 25 mL/min; Detector, 254nm]. The collected fraction was combined and concentrated under vacuumto afford the desired racemic product (60 mg, 24% yield) as a whitesolid.

Step 2. Chiral Separation

The racemate (60 mg) was resolved by Chiral-Prep-HPLC with the followingconditions [Column: AD-H; Mobile phase A: 5% hexane, Mobile phase B:ethanol; Gradient: 5% ethanol; 25 mL/min; Detector, 254 nm]. Thecollected fraction was combined and concentrated under vacuum to affordthe desired product 5A (15.3 mg, 26% yield, RT=4.33 min) and 5B (13.3mg, 22% yield, RT=5.45 min) as a white solid.

Compound 5A: LCMS (ES, m/z): 472.5 [M+H]⁺. ¹HNMR (300 MHz, DMSO-d₆): δ9.30 (s, 1H), 8.06 (s, 1H), 7.95-7.86 (m, 1H), 7.80 (d, J=1.8 Hz, 1H),7.33-7.28 (m, 1H), 7.16-7.14(m, 1H), 7.07-7.01(m, 1H), 6.85 (dd, J=8.4,1.8 Hz, 1H), 4.45-4.42 (m, 1H), 2.65 (d, J=6.6 Hz, 4H), 1.70-1.59 (m,5H), 0.83 (d, J=6.6 Hz, 12H).

Compound 5B: LCMS (ES, m/z): 472.5 [M+H]⁺. ¹HNMR (300 MHz, DMSO-d₆): δ9.29 (s, 1H), 8.05 (s, 1H), 7.95-7.87 (m, 1H), 7.80 (d, J=2.1 Hz, 1H),7.33-7.26 (m, 1H), 7.15-7.12(m, 1H), 7.07-7.01(m, 1H), 6.85 (dd, J=8.4,1.8 Hz, 1H), 4.44-4.38 (m, 1H), 2.64 (d, J=6.6 Hz, 4H), 1.67-1.56(m,5H), 0.83 (d, J=6.6 Hz, 12H).

Example 6

Step 1. Synthesis of 6-1

To a solution of2-[4-[bis(2-methylpropyl)amino]-3-nitrophenyl]acetonitrile (2.0 g, 6.91mmol) in acetonitrile (30 mL) was added selectfluor (4.9 g, 13.84 mmol)portionwise. The resulted mixture was stirred at room temperature for 6h. The reaction was then concentrated under vacuum. The residue waspurified by silica gel column with ethyl acetate/petroleum ether (1/10)as eluent to afford the desired product (0.55 g, 26%).

Step 2. Synthesis of 6-2

To a solution of2-[4-[bis(2-methylpropyl)amino]-3-fluoro-5-nitrophenyl]acetonitrile (550mg, 1.79 mmol) in acetic acid (5 mL) was added iron (1.0 g, 17.86 mmol).The reaction was stirred at room temperature for 1 h. The mixture wasfiltered through Celite and the filtrate was concentrated under vacuum.The residue was dissolved in ethyl acetate (50 mL), washed withsaturated aqueous sodium bicarbonate (20 mL) and water (20 mL). Theorganic phase was concentrated under vacuum, and the residue waspurified by silica gel column with ethyl acetate/petroleum ether (1/10)as eluent to afford the desired product (0.4 g, 81%).

Step 3. Synthesis of 6-3

To a solution of2-[3-amino-4-[bis(2-methylpropyl)amino]-5-fluorophenyl]acetonitrile (190mg, 0.68 mmol) in tetrahydrofuran (3 mL) was added2,4-difluoro-1-isocyanatobenzene (160 mg, 1.03 mmol) and triethylamine(0.21 g, 2.04 mmol). The mixture was then stirred at room temperaturefor 3 h. The reaction was diluted with ethyl acetate (20 mL), and thenwashed with water (10 mL×2). The organic phase was concentrated undervacuum. The residue was purified by silica gel column with ethylacetate/petroleum ether (1/2) as eluent to afford the desired product(0.14 g, 47%).

Step 4. Synthesis of 6

A solution of3-[2-[bis(2-methylpropyl)amino]-5-(cyanomethyl)-3-fluorophenyl]-1-(2,4-difluorophenyl)urea(140 mg, 0.32 mmol), trimethylsilyl azide (300 mg, 2.60 mmol) andtetrabutylammonium fluoride (500 mg, 1.91 mmol) in toluene (3 mL) wasstirred at 90° C. for 1 h. The mixture was cooled to room temperatureand diluted with ethyl acetate (20 mL). The mixture was washed withwater (10 mL×2). The organic phase was concentrated under vacuum. Theresidue (420 mg) was purified by Prep-HPLC with the followingconditions: [Column, X Bridge Shield RP18 OBD Column, 5 um, 19*150 mm;mobile phase, water (0.05% TFA) and ACN/MeOH (15% up to 60.0% in 8 min);Detector, UV 254 nm] to afford the desired product (36.2 mg, 24%) as anoff white solid. LCMS (ES, m/z): 476.4 [M+H]⁺; ¹HNMR: (300 MHz, DMSO-d₆,ppm): δ 9.43 (s, 1H), 8.34 (s, 1H), 7.93-7.84 (m, 1H), 7.79 (s, 1H),7.73-7.68 (m, 1H), 7.34-7.26 (m, 1H), 7.07-7.05 (m, 1H), 6.67 (dd,J=11.4 Hz, 1.5 Hz, 1H), 4.11 (s, 2H), 3.51-3.42 (m, 2H), 2.79 (m, 4H),0.83 (d, J=4.5 Hz, 12H).

Example 7

Step 1. Synthesis of 7-2

To a solution of 2-(4-fluorophenyl)acetonitrile (8 g, 59.20 mmol) intoluene (160 mL) at 0° C., were added 1,2-dibromoethane (11.28 g, 60.04mmol), potassium hydroxide (27 g, 481.20 mmol, 8.00 equiv), tetrabutylammonium bromide (200 mg, 0.62 mmol) and water (8 mL). The reactionmixture was heated to 100° C. and stirred for 1.5 h. The reaction wascooled down, quenched with water (100 mL), and extracted with ethylacetate (100 mL×3). The combined organic layer was dried over anhydroussodium sulfate and concentrated under vacuum. The residue was purifiedby silica gel column with ethyl acetate/petroleum ether (1/10) as eluentto afford 1-(4-fluorophenyl) cyclopropane-1-carbonitrile (5 g, 52%).

Step 2. Synthesis of 7-3

To a solution of 1-(4-fluorophenyl)cyclopropane-1-carbonitrile (5 g,31.02 mmol) in sulfuric acid (100 mL) at 0° C., was added potassiumnitrate(4.7 g, 46.49 mmol). The mixture was then warmed up to roomtemperature and stirred for 40 min. The reaction was quenched withwater/ice (300 mL) and the mixture was extracted with ethyl acetate (100mL×3). The organic layer was washed with saturated aqueous sodiumbicarbonate (30 mL×3), dried over anhydrous sodium sulfate andconcentrated under vacuum. The residue was purified by silica gel columnchromatography with ethyl acetate/petroleum ether (1/4) as eluent toafford 1-(4-fluoro-3-nitrophenyl) cyclopropane-1-carbonitrile (1.6 g,25%).

Step 3. Synthesis of 7-4

To a solution of 1-(4-fluoro-3-nitrophenyl) cyclopropane-1-carbonitrile(1.6 g, 7.76 mmol) and N,N-diisopropylethylamine (2 g, 15.48 mmol) indimethylsufoxide (50 mL), was added bis(2-methylpropyl)amine (1.2 g,9.28 mmol). The mixture was stirred at 100° C. for 2.5 h. The reactionwas cooled down, quenched with water (150 mL), and extracted with ethylacetate (100 mL×3). The organic layer was dried over anhydrous sodiumsulfate and concentrated under vacuum. The residue was purified bysilica gel column with ethyl acetate/petroleum ether (1/8) to afford1-[4-[bis (2-methylpropyl) amino]-3-nitrophenyl]cyclopropane-1-carbonitrile (1.94 g, 79%).

Step 4. Synthesis of 7-5

A mixture of 1-[4-[bis(2-methylpropyl)amino]-3-nitrophenyl]cyclopropane-1-carbonitrile (1.9 g, 6.02 mmol) and palladium on carbon(0.19 g) in methanol (20 mL) was stirred under hydrogen atmosphere (1atm) at room temperature for 2 h. The mixture was filtered throughCelite and the filtrate was concentrated under vacuum. The residue waspurified by silica gel column with ethyl acetate/petroleum ether (1/8)to afford1-[3-amino-4-[bis(2-methylpropyl)amino]phenyl]cyclopropane-1-carbonitrile(1.0 g, 58%).

Step 5. Synthesis of 7-6

A mixture of1-[3-amino-4-[bis(2-methylpropyl)amino]phenyl]cyclopropane-1-carbonitrile(500 mg, 1.75 mmol) and potassium hydroxide (5 mL, 3 M in H₂O) inethanol (10 mL) was stirred in a sealed tube at 100° C. for overnight.After cooled to the room temperature, the pH value of the solution wasadjusted to 7 with aqueous hydrogen chloride (2 N) and the mixture wasthen extracted with ethyl acetate (30 mL×3). The organic phase was driedover anhydrous sodium sulfate and concentrated under vacuum to afford1-[3-amino-4-[bis(2-methylpropyl)amino]phenyl]cyclopropane-1-carboxylicacid (530 mg, 99%).

Step 6. Synthesis of 7

To a solution of 1-[3-amino-4-[bis(2-methylpropyl)amino]phenyl]cyclopropane-1-carboxylic acid (530 mg, 1.74 mmol) and2,4-difluoro-1-isocyanatobenzene (324 mg, 2.09 mmol) in tetrahydrofuran(353 mg, 4.89 mmol), was added triethylamine (5 mL). The reactionmixture was stirred at 25° C. for 3 h. The resulting mixture wasconcentrated under vacuum and then purified by prep-HPLC (Column:XBridge Shield RP18 OBD Column, 5 um, 19×150 mm; Mobile Phase A: Waterwith 0.05% NH₄HCO₃, Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient:25% B to 85% B in 8 min; detector: UV 254 nm) to afford1-[4-[bis(2-methylpropyl)amino]-3-[[(2,4-difluorophenyl)carbamoyl]amino]phenyl]cyclopropane-1-carboxylicacid (146.8 mg, 18% yield). LRMS: (ES, m/z): [M+H]^(|)=460.3. ¹HNMR (300MHz, DMSO-d₆): δ 12.25 (s, br, 1H), 9.29 (s, 1H), 8.04 (s, 1H),7.96-7.85 (m, 1H), 7.84 (s, 1H), 7.34-7.26 (m, 1H), 7.10 (d, J=8.1 Hz,1H), 7.09-6.93 (m, 1H), 6.91 (d, J=2.1 Hz, 1H), 2.65 (d, J=6.9 Hz, 4H),1.70-1.59 (m, 2H), 1.42-1.39 (m, 2H), 1.09-1.05 (m, 2H), 0.86 (d, J=6.6Hz, 12H).

Example 8

Step 1. Synthesis of 8-2

To a solution of 2-(4-fluorophenyl)acetonitrile (5 g, 37 mmol) inN,N-dimethylformamide (20 mL) at 0° C., was added sodium hydride (3.7 g,154 mmol). The reaction was then warmed to room temperature and stirredfor 30 min. The reaction mixture was cooled to 0° C. again and1-bromo-2-(2-bromoethoxy)ethane (8.59 g, 37 mmol) was added. Thereaction was then stirred at room temperature overnight. Water (100 mL)was added and the mixture was extracted with ethyl acetate (50 mL×3).The organic layer was dried over anhydrous sodium sulfate andconcentrated under vacuum. The residue was purified by silica gel columnwith ethyl acetate/petroleum ether (1/9) as eluent to afford4-(4-fluorophenyl)oxane-4-carbonitrile (3.69 g, 49%).

Step 2. Synthesis of 8-3

To a solution of 4-(4-fluorophenyl)oxane-4-carbonitrile (3.69 g, 17.98mmol) in sulfuric acid (30 mL) at 0° C., was added potassium nitrate(2.73 g, 27.00 mmol). The reaction mixture was then stirred at 25° C.for 1 h. The reaction was quenched by addition of water/ice (250 mL) andthe mixture was extracted with ethyl acetate (50 mL×3). The organiclayer was washed with saturated aqueous sodium bicarbonate (20 mL×2),dried over anhydrous sodium sulfate and concentrated under vacuum. Theresidue was purified by silica gel column chromatography with ethylacetate/petroleum ether (1/9) as eluent to afford4-(4-fluoro-3-nitrophenyl)oxane-4-carbonitrile (2.38 g, 53%).

Step 3. Synthesis of 8-4

To a solution of 4-(4-fluoro-3-nitrophenyl)oxane-4-carbonitrile (2.30 g,9.19 mmol) and diisopropylethylamine (2.37 g, 18.37 mmol) indimethylsulfoxide (10 mL), was added bis(2-methylpropyl)amine (1.42 g,11.02 mmol). The reaction mixture was then warmed to 100° C. and stirredfor 4.5 h. The reaction was quenched by addition of water (100 mL) andthe mixture was extracted with ethyl acetate (100 mL×3). The organiclayer was dried over anhydrous sodium sulfate and concentrated undervacuum. The residue was purified by silica gel column with ethylacetate/petroleum ether (1/5) to afford 4-[4-[bis(2-methylpropyl)amino]-3-nitrophenyl] oxane-4-carbonitrile (2.7 g, 82%).

Step 4. Synthesis of 8-5

A mixture of4-[4-[bis(2-methylpropyl)amino]-3-nitrophenyl]oxane-4-carbonitrile (2.7g, 7.51 mmol) and palladium on carbon (0.3 g) in methanol (50 mL) wasstirred under hydrogen atmosphere (1 atm) at 25° C. for 4.5 h. Then thereaction mixture was filtered through celite and the filtrate wasconcentrated under vacuum. The residue was purified by silica gel columnwith ethyl acetate/petroleum ether (1/4) to afford4-[3-amino-4-[bis(2-methylpropyl) amino]phenyl]oxane-4-carbonitrile(1.62 g, 65%).

Step 5. Synthesis of 8-6

A mixture of4-[3-amino-4-[bis(2-methylpropyl)amino]phenyl]oxane-4-carbonitrile (500mg, 1.52 mmol) and potassium hydroxide (3 M in H₂O, 5 mL) in ethanol (10mL) was stirred in a sealed tube at 100° C. for 2 days. Water (50 mL)was added and the mixture was extracted with ethyl acetate (50 mL×3).The organic phase was dried over anhydrous sodium sulfate andconcentrated under vacuum to afford4-[3-amino-4-[bis(2-methylpropyl)amino]phenyl]oxane-4-carboxylic acid(520 mg, 98%).

Step 6. Synthesis of 8

A mixture of4-[3-amino-4-[bis(2-methylpropyl)amino]phenyl]oxane-4-carboxylic acid(520 mg, 1.49 mmol), 2,4-difluoro-1-isocyanatobenzene (279 mg, 1.80mmol) and triethylamine (303 mg, 2.99 mmol) in tetrahydrofuran (5 mL)was stirred at 25° C. for 3 h. Water (20 mL) was added and the mixturewas extracted with ethyl acetate (50 mL×3). The organic layer wasconcentrated and the residue was purified by prep-HPLC (Column: XBridgeShield RP18 OBD Column, 5 um, 19×150 mm; Mobile Phase A: Water with0.05% NH₄HCO₃, Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 25%B to 85% B in 8 min; detector: UV 254 nm) to afford4-[4-[bis(2-methylpropyl)amino]-3-[[(2,4-difluorophenyl)carbamoyl]amino]phenyl]oxane-4-carboxylicacid (88.56 mg, 12%) as a white solid. LRMS (ES, m/z): [M+H]⁺=504.5.¹HNMR (300 MHz, DMSO-d₆) δ 9.30 (s, 1H), 8.04 (s, 1H), 7.97-7.89 (m,2H), 7.34-7.26 (m, 1H), 7.15 (d, J=8.4 Hz, 1H), 7.07-6.98 (m, 2H), 3.80(d, J=11.7, 2H), 3.54-3.41 (m, 2H), 2.66 (d, J=6.9 Hz, 4H), 2.34 (d,J=13.2 Hz, 2H), 1.75-1.60, (m, 4H), 0.84 (d, J=6.6 Hz, 12H).

Example 9

Step 1. Synthesis of 9-1

Into a 250-mL 3-necked round-bottom flask, was placed a solution of2-[4-[bis(2-methylpropyl)amino]-3-nitrophenyl]acetonitrile (5 g, 17.28mmol) in DMSO (100 mL), followed by addition of sodium hydride (2.77 g,69.25 mmol) in portions at 10° C. The resulting mixture was stirred atroom temperature for 1 h. 1,4-Dibromobutane (7.47 g, 34.60 mmol) wasadded dropwise in 5 min with stirring at 10° C. The resulting solutionwas stirred at room temperature for overnight. The reaction was thenquenched by addition of 50 mL of water, and extracted with 3×100 mL ofethyl acetate. The combined organic layer was washed with 3×100 mL ofbrine. The mixture was dried over anhydrous sodium sulfate andconcentrated under vacuum. The residue was applied onto a silica gelcolumn with ethyl acetate/petroleum ether (1:10˜1:3) to afford1-[4-[bis(2-methylpropyl)amino]-3-nitrophenyl]cyclopentane-1-carbonitrile(2.5 g, 42% yield).

Step 2. Synthesis of 9-2

Into a 50-mL round-bottom flask, was placed methanol (10 mL),1-[4-[bis(2-methylpropyl)amino]-3-nitrophenyl]cyclopentane-1-carbonitrile(1 g, 2.91 mmol), and sulfuric acid (5 mL). The resulting solution washeated to reflux for 48 h. The reaction was cooled to room temperature.The pH value of the solution was adjusted to 8 with sodium carbonate(10% aqueous solution). The resulting mixture was extracted with 3×50 mLof ethyl acetate. The combined organic phase was washed with 3×50 mL ofbrine, dried over anhydrous sodium sulfate, and concentrated undervacuum. The residue was applied onto a silica gel column with ethylacetate/petroleum ether (1:20˜1:5) to afford methyl1-[4-[bis(2-methylpropyl)amino]-3-nitrophenyl]cyclopentane-1-carboxylate(450 mg, 41% yield).

Step 3. Synthesis of 9-3

To a solution of methyl1-[4-[bis(2-methylpropyl)amino]-3-nitrophenyl]cyclopentane-1-carboxylate(450 mg, 1.20 mmol) in methanol (5 mL), was added palladium on carbon(500 mg). The flask was evacuated and flushed three times with nitrogen,followed by flushing with hydrogen. The mixture was stirred at roomtemperature under an atmosphere of hydrogen (balloon) for 3 h. The solidwas filtered out. The resulting mixture was concentrated under vacuum.The residue was applied onto a silica gel column with ethylacetate/petroleum ether (1:10-1:1) to afford methyl1-(3-amino-4-(diisobutylamino)phenyl)cyclopentanecarboxylate (350 mg,85% yield).

Step 4. Synthesis of 9-4

Into a 25-mL round-bottom flask, was placed tetrahydrofuran (5 mL),methyl1-[3-amino-4-[bis(2-methylpropyl)amino]phenyl]cyclopentane-1-carboxylate(350 mg, 1.01 mmol), triethylamine (202 mg, 2.00 mmol), and2,4-difluoro-1-isocyanatobenzene (188 mg, 1.21 mmol). The resultingsolution was stirred at room temperature for 4 h. The reaction wasconcentrated under vacuum. The residue was applied onto a silica gelcolumn with ethyl acetate/petroleum ether (1:10-1:3) to afford methyl1-[4-[bis(2-methylpropyl)amino]-3-[[(2,4-difluorophenyl)carbamoyl]amino]phenyl]cyclopentane-1-carboxylate(250 mg, 49% yield).

Step 5. Synthesis of 9

Into a 25-mL round-bottom flask, was placed a solution of methyl1-[4-[bis(2-methylpropyl)amino]-3-[[(2,4-difluorophenyl)carbamoyl]amino]phenyl]cyclopentane-1-carboxylate(250 mg, 0.50 mmol) in methanol (5 mL), and sodium hydroxide (1 mL, 15%aq.). The resulting solution was stirred at room temperature for 4 h.The resulting mixture was concentrated under vacuum. The pH value of thesolution was adjusted to 6 with hydrogen chloride (1 N). The resultingsolution was extracted with 3×10 mL of ethyl acetate. The combinedorganic layers was washed with 3×10 mL of brine, and concentrated undervacuum. The crude product was purified by Flash-Prep-HPLC with thefollowing conditions: Column: SunFire C18 5 um 19*150 mm; mobile phase;CH₃CN/water (0.05% NH₃H₂O; Gradient: 51% to 65% in 7 min; Flow rate: 20mL/min; Detector, UV 254 nm. This resulted in 79.5 mg (33% yield) of1-[4-[bis(2-methylpropyl)amino]-3-[[(2,4-difluorophenyl)carbamoyl]amino]phenyl]cyclopentane-1-carboxylicacid as an off-white solid. LCMS: (ES, m/z): 488.3 [M+H]⁺. HNMR: (300MHz, DMSO-d₆, ppm): δ 12.10 (s, 1H), 9.25 (s, 1H), 8.03 (s, 1H),7.95-7.87 (m, 2H), 7.31 (t, J=2.7 Hz, 1H), 7.12 (d, J=8.4 Hz, 1H),7.07-7.00 (m, 1H), 6.94 (dd, J=8.4, 2.4 Hz, 1H), 2.65 (d, J=6.9 Hz, 4H),2.49-2.45 (m, 2H), 1.76-1.58 (m, 8H), 0.84 (d, J=6.6 Hz, 12H).

Example 10

Step 1. Synthesis of 10-1

Into a 100-mL round-bottom flask, was placed a solution of1-[4-[bis(2-methylpropyl)amino]-3-nitrophenyl]cyclopentane-1-carbonitrile(1.5 g, 4.37 mmol) in ethanol (30 mL), Fe (1.47 g, 26.25 mmol), andNH₄Cl (162 mg, 3.03 mmol). The resulting solution was stirred at 80° C.for 3 h. The reaction mixture was cooled to room temperature. The solidwas filtered out and the filtrate was concentrated under vacuum. Theresidue was dissolved in 150 mL of ethyl acetate, washed with water (50mL) and brine (3×50 mL), dried over anhydrous sodium sulfate, andconcentrated under vacuum. The residue was applied onto a silica gelcolumn with ethyl acetate/petroleum ether (1:10-1:1) to afford1-[3-amino-4-[bis(2-methylpropyl)amino]phenyl]cyclopentane-1-carbonitrile(600 mg, 44% yield).

Step 2. Synthesis of 10-2

Into a 50-mL 3-necked round-bottom flask, was placed tetrahydrofuran (10mL), triethylamine (387 mg, 3.82 mmol), and1-[3-amino-4-[bis(2-methylpropyl)amino]phenyl]cyclopentane-1-carbonitrile(600 mg, 1.91 mmol). This was followed by addition of2,4-difluoro-1-isocyanatobenzene (356 mg, 2.30 mmol) dropwise withstirring at 0° C. The resulting solution was stirred at room temperaturefor 3 h. The reaction was concentrated under vacuum. The residue wasapplied onto a silica gel column with ethyl acetate/petroleum ether(1:20˜1:3) to afford3-[2-[bis(2-methylpropyl)amino]-5-(1-cyanocyclopentyl)phenyl]-1-(2,4-difluorophenyl)urea(500 mg, 56% yield).

Step 3. Synthesis of 10

Into a 50-mL 2-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed azidosodium (62 mg, 0.95 mmol),and toulene (3 mL). This was followed by addition of diethylaluminumchloride (0.9M) (1.07 mL) dropwise with stirring at 0° C. The resultingsolution was stirred at room temperature for 7 h. To this was added asolution of1-[2-[bis(2-methylpropyl)amino]-5-(1-cyanocyclopentyl)phenyl]-3-(2,4-difluorophenyl)urea(300 mg, 0.64 mmol) in toluene (1 mL). The resulting solution was heatedand stirred at 120° C. overnight. The reaction was cooled to roomtemperature and quenched by addition of 10 mL of water. The resultingsolution was extracted with 3×50 mL of ethyl acetate. The combinedorganic layers was washed with 3×50 mL of brine, dried over anhydroussodium sulfate, and concentrated under vacuum. The crude product waspurified by Prep-HPLC with the following conditions: Column, waterssunfire C18 19*150 mm 5 um; mobile phase, CH₃CN/Water (0.05%TFA),65%-74% (7 min); Detector, 254 nm. This resulted in 60 mg (15% yield) of3-[2-[bis(2-methylpropyl)amino]-5-[1-(1H-1,2,3,4-tetrazol-5-yl)cyclopentyl]phenyl]-1-(2,4-difluorophenyl)ureaas a trifluoroacetic acid salt. LCMS. (ES, m/z): 512 [M+H—CF₃COOH]⁺.HNMR (300 MHz, DMSO-d₆, ppm) δ 9.29 (s, 1H), 8.02 (s, 1H), 7.94-7.86 (m,2H), 7.30 (t, J=6.0 Hz, 1H), 7.27 (d, J=6.3 Hz, 1H), 7.11-7.02 (m, 1H),6.85 (dd, J=8.4, 2.1 Hz, 1H), 2.73-2.63 (m, 6H), 2.18-2.13 (m, 2H),1.76-1.66 (m, 2H), 1.66-1.60 (m, 2H), 1.58-1.49 (m, 2H), 0.82 (d, J=6.6Hz, 12H).

Example 11

Step 1. Synthesis of 11-1

To a solution of 2-(4-fluorophenyl)acetonitrile (20.0 g, 148 mmol) intetrahydrofuran (200 mL) at 0° C., was added sodium hydride (17.8 g, 440mmol) in portions. The mixture was then stirred at 0° C. for 30 min. Asolution of 1,4-dibromobutane (38.4 g, 178 mmol) in tetrahydrofuran (100mL) was added dropwise, and the reaction mixture was stirred at roomtemperature for another 4 h. The reaction was then cooled to 0° C., andquenched by addition of water (10 mL). The resulted mixture was dilutedwith ethyl acetate (1 L), and was washed with water (600 mL) and brine(600 mL). The combined organic phase was dried over anhydrous sodiumsulfate, and concentrated under vacuum. The residue was purified bysilica gel column with ethyl acetate/petroleum ether (1/8) as the eluentto afford the desired product (22.1 g, 71% yield).

Step 2. Synthesis of 11-2

To a solution of 1-(4-fluorophenyl)cyclopentanecarbonitrile (22.1 g, 117mmol) in concentrated sulfuric acid (200 mL) at 0° C., was addedpotassium nitrate (17.7 g, 175 mmol) portionwise. The resulting mixturewas then stirred at 0° C. for 10 min. The reaction was poured into icewater (1 L) carefully. The mixture was extracted with ethyl acetate (600mL×2), dried over anhydrous sodium sulfate, and concentrated undervacuum. The residue was purified by silica gel column with ethylacetate/petroleum ether (1/6) as the eluent to afford the desiredproduct (15.2 g, 55% yield).

Step 3. Synthesis of 11-3

To a solution of cyclohexanamine (5 g, 50.42 mmol) and triethylamine (8mL) in tetrahydrofuran (45 mL) at 0° C., was added 2-methylpropanoylchloride (5 g, 46.93 mmol) dropwise. The mixture was then stirred atroom temperature for 3 days. The reaction was quenched byaddition ofsaturated ammonium chloride (150 mL), and extracted with dichloromethane(150 mL). The combined organic phase was washed with brine (200 mL×2),dried over anhydrous sodium sulfate, and concentrated under vacuum toafford the desired product (7.5 g, 88% yield).

Step 4. Synthesis of 11-4

To a solution of N-cyclohexyl-2-methylpropanamide (7 g, 41.36 mmol) intetrahydrofuran (140 mL) at 0° C., was added lithium aluminiumtetrahydride (6.5 g, 171.28 mmol) in several portions. The mixture wasthen stirred at 70° C. for overnight. The mixture was cooled to 0° C.and quenched by the addition of saturated ammonium chloride (250 mL).The solid was filtered out and filter cake was washed with ethyl acetate(200 mL×2). The combined organic phase was separated and washed withbrine (300 mL×2), dried over anhydrous sodium sulfate, and concentratedunder vacuum to afford the desired product (4 g, 62% yield).

Step 5. Synthesis of 11-5

To a solution of 1-(4-fluoro-3-nitrophenyl)cyclopentane-1-carbonitrile(1 g, 4.27 mmol) in dimethyl sufoxide (20 mL), was addedN-(2-methylpropyl)cyclohexanamine (1 g, 6.44 mmol) andN,N-diisopropylethylamine (1.65 g, 12.77 mmol) sequentially. The mixturewas then stirred at 100° C. for 16 h. The reaction was cooled to roomtemperature and diluted with water (100 mL). The mixture was extractedwith ethyl acetate (100 mL×3), and washed with brine (100 mL×5). Theorganic phase was dried over anhydrous sodium sulfate, and concentratedunder vacuum. The residue was purified by silica gel column with ethylacetate/petroleum ether (1/99) to afford the desired product (1 g, 63%yield).

Step 6. Synthesis of 11-6

To a solution of1-[4-[cyclohexyl(2-methylpropyl)amino]-3-nitrophenyl]cyclopentane-1-carbonitrile(1 g, 2.71 mmol) in acetic acid (10 mL) was added iron (1.5 g, 26.86mmol). The mixture was then stirred at room temperature for 1 h. Ethylacetate (150 mL) was added and the solid was filtered off. The filtratewas diluted with water (100 mL), and the pH value was adjusted to 9 byaddition of saturated aqueous sodium bicarbonate. The organic phase wasseparated and washed with brine (100 mL×2), dried over anhydrous sodiumsulfate, and concentrated under vacuum. The residue was purified bysilica gel column with ethyl acetate/petroleum ether (1/25-1/20) toafford the desired product (597 mg, 65% yield).

Step 7. Synthesis of 11-7

To a solution of1-[3-amino-4-[cyclohexyl(2-methylpropyl)amino]phenyl]cyclopentane-1-carbonitrile(200 mg, 0.589 mmol) in ethanol (10 mL) and water (2 mL), was addedpotassium hydroxide (3 g, 53.47 mmol). The mixture was then stirred at100° C. for 3 days. The mixture was cooled to room temperature andconcentrated under vacuum. The residue was dissolved in water (50 mL)and the pH value was adjusted to 6 with hydrogen chloride (1 N). Themixture was extracted with dichloromethane (50 mL×2), and washed withbrine (30 mL×2). The organic phase was dried over anhydrous sodiumsulfate and concentrated under vacuum. The residue was purified byFlash-Prep-HPLC with the following conditions: [Column, C18 silica gel;mobile phase (A: MeCN, B: H₂O (0.1% TFA), MeCN=50%; Detector, UV 254 nm)to afford the desired product (85 mg, 40% yield).

Step 8. Synthesis of 11

To a solution of1-[3-amino-4-[cyclohexyl(2-methylpropyl)amino]phenyl]cyclopentane-1-carboxylicacid (85 mg, 0.24 mmol) in tetrahydrofuran (50 mL), was added2,4-difluoro-1-isocyanatobenzene (51 mg, 0.33 mmol) and triethylamine(111 mg, 1.10 mmol) sequentially. The reaction was then stirred at roomtemperature for 2 h. The mixture was concentrated under vacuum. Theresidue was re-dissolved in water (50 mL), and the pH value was adjustedto 6 with HCl (1 N). The mixture was extracted with dichloromethane (50mL×2), and washed with brine (30 mL×2). The organic phase was dried overanhydrous sodium sulfate, and concentrated under vacuum. The residue waspurified by Flash-Prep-HPLC with the following conditions: [Column, C18silica gel; mobile phase (A: MeCN, B: H₂O), MeCN=96%; Detector, UV 254nm] to afford the desired product (26.6 mg, 22% yield) as a white solid.LCMS (ES, m/z): 514.50 [M+1]⁺; ¹HNMR (300 MHz, DMSO-D₆, ppm): δ 12.23(s, 1H), 9.37 (t, J=4.6 Hz, 1H), 8.14 (s, 1H), 7.99 (d, J=2.2 Hz, 1H),7.90 (td, J=9.2, 6.2 Hz, 1H), 7.32 (td, J=8.8, 4.5 Hz, 1H), 7.22-6.99(m, 2H), 6.99-6.85 (m, 1H), 2.76 (d, J=7.3 Hz, 2H), 1.90-1.80 (m, 2H),1.77-1.47 (m, 9H), 1.40-1.00 (m, 9H), 0.82 (d, J=6.5 Hz, 6H).

Example 12

Step 1. Synthesis of 12-1

A solution of 1-(4-fluoro-3-nitrophenyl)cyclopentane-1-carbonitrile (1.5g, 6.40 mmol), 4,4-difluorocyclohexan-1-amine (950 mg, 7.03 mmol) andN,N-diisopropylethylamine (1.65 g) in dimethylsufoxide (20 mL) wasstirred at 100° C. for overnight. The mixture was cooled to roomtemperature, diluted with ethyl acetate (80 mL), and washed with water(60 mL) and brine (60 mL). The organic phase was dried over anhydroussodium sulfate and concentrated under vacuum. The residue was purifiedby silica gel column with ethyl acetate/petroleum ether (1/10) as theeluent to afford the desired product (2.1 g, 94% yield).

Step 2. Synthesis of 12-2

To a solution of1-[4-[(4,4-difluorocyclohexyl)amino]-3-nitrophenyl]cyclopentane-1-carbonitrile(2.1 g, 6.01 mmol) in tetrahydrofuran (25 mL) was added sodium hydride(720 mg, 18.00 mmol) in portions at 0° C. The mixture was then stirredat 0° C. for 30 min followed by addition of a solution of3-bromo-2-methylprop-1-ene (1.22 g, 9.04 mmol) in tetrahydrofuran (5mL). The reaction was then stirred at room temperature for overnight.The mixture was quenched by addition of saturated ammonium chloridesolution (5 mL) at 0° C., and then diluted with 80 mL of ethyl acetate.The organic phase was washed with water (60 mL) and brine (60 mL), driedover anhydrous sodium sulfate, and concentrated under vacuum. Theresidue was purified by silica gel column with ethyl acetate/petroleumether (1/15) as the eluent to afford the desired product (1.0 g, 41%yield).

Step 3. Synthesis of 12-3

To a solution of1-[4-[(4,4-difluorocyclohexyl)(2-methylprop-2-en-1-yl)amino]-3-nitrophenyl]cyclopentane-1-carbonitrile(1.0 g, 2.48 mmol) in acetic acid (10 mL) was added iron (690 mg, 12.32mmol). The mixture was then stirred at room temperature for 30 min.Ethyl acetate (60 mL) was added and the solid was filtered off. Thereaction mixture was washed with saturated aqueous sodium bicarbonate(30 mL×3), water (30 mL) and brine (30 mL). The organic phase was driedover anhydrous sodium sulfate and concentrated under vacuum. The residuewas purified by silica gel column with ethyl acetate/petroleum ether(1/8) as the eluent to afford the desired product (0.8 g, 86% yield).

Step 4. Synthesis of 12-4

To a solution of1-[3-amino-4-[(4,4-difluorocyclohexyl)(2-methylprop-2-en-1-yl)amino]phenyl]cyclopentane-1-carbonitrile(280 mg, 0.75 mmol) in ethyl acetate (3 mL) was added palladium oncarbon (28 mg) and triethylamine (0.3 mL). The reaction was then stirredunder hydrogen balloon at room temperature for 30 min. The mixture wasfiltered through Celite and the filtrate was concentrated under vacuum.The residue was purified by silica gel column with ethylacetate/petroleum ether (1/8) to afford the desired product (0.16 g, 57%yield).

Step 5. Synthesis of 12-5

To a solution of1-[3-amino-4-[(4,4-difluorocyclohexyl)(2-methylpropyl)amino]phenyl]cyclopentane-1-carbonitrile(160 mg, 0.43 mmol) in ethanol (4 mL) and water (1 mL) was addedpotassium hydroxide (1.12 g, 19.96 mmol). The mixture was then stirredat 100° C. for 2 days. The mixture was cooled to room temperature anddiluted with water (10 mL), extracted with ethyl acetate (10 mL×2), andwashed with brine (10 mL). The organic phase was dried over anhydroussodium sulfate and concentrated under vacuum to afford the desiredproduct (90 mg, 54% yield).

Step 6. Synthesis of 12

A solution of1-[3-amino-4-[(4,4-difluorocyclohexyl)(2-methylpropyl)amino]phenyl]cyclopentane-1-carboxylicacid (90 mg, 0.23 mmol), 2,4-difluoro-1-isocyanatobenzene (53 mg, 0.34mmol) and triethylamine (69 mg, 0.69 mmol) in tetrahydrofuran (3 mL) wasstirred at room temperature for 0.5 h. Ethyl acetate (20 mL) was thenadded and the organic phase was washed with water (10 mL) and brine(10mL). The organic phase was dried over anhydrous sodium sulfate andconcentrated under vacuum. The residue was purified by Prep-HPLC withthe following conditions: [Column: X Bridge Shield RP18 OBD Column, 5um,19*150 mm; mobile phase, Waters (10 MMOL/L NH₄HCO₃) and ACN (35.0%ACN up to 70.0% in 8 min); Detector, 254 nm] to afford the desiredproduct (52.1 mg, 42% yield) as an off-white solid. LCMS (ES, m/z):550.50 [M+H]⁺; ¹HNMR (300 MHz, DMSO-d₆, ppm): δ 9.40 (s, 1H), 8.24 (s,1H), 8.09 (d, J=2.1 Hz, 1H), 7.96-7.88 (m, 1H), 7.35-7.27 (m, 1H),7.15-6.94 (m, 3H), 2.89-2.76 (m, 3H), 2.08-1.24 (m, 17H), 0.82 (d, J=6.6Hz, 6H).

Example 13

Step 1. Synthesis of 13-2

To a solution of lithium aluminium tetrahydride (3.0 g, 88.44 mmol) intetrahydrofuran (30 mL) at 0° C., was added a solution of4-(trifluoromethoxy)benzonitrile (5.0 g, 26.72 mmol) in tetrahydrofuran(30 mL) dropwise. The reaction was then stirred at room temperature for3 h. The mixture was diluted with tetrahydrofuran (50 mL) at 0° C., thenquenched by the addition of water (3 mL), 15% sodium hydroxide (3 mL)and water (3 mL). The mixture was stirred at room temperature for 15min. The mixture was filtered through Celite and the filtrate was driedover anhydrous magnesium sulfate and concentrated under vacuum to affordthe desired product (3.1 g, 61% yield).

Step 2. Synthesis of 13-3

To a solution of 3,3,3-trifluoropropanoic acid (2.28 g, 17.81 mmol) andN,N-diisopropylethylamine (4.2 g) in N,N-dimethylformamide (25 mL), wasadded HATU (9.25 g) in portions at 0° C. The mixture was then stirredfor 5 min at 0° C., followed by addition of a solution of[4-(trifluoromethoxy)phenyl]methanamine (3.1 g, 16.22 mmol) inN,N-dimethylformamide (25 mL). The reaction was allowed to warm to roomtemperature and stirred for another 3 h. Water (300 mL) was added, andthe mixture was extracted with ethyl acetate (200 mL×3). The combinedorganic phase was dried over anhydrous sodium sulfate and concentratedunder vacuum. The residue was purified by silica gel column with ethylacetate/petroleum ether (1/2) as the eluent to afford the desiredproduct (2.4 g, 49% yield).

Step 3. Synthesis of 13-4

A solution of3,3,3-trifluoro-N-[[4-(trifluoromethoxy)phenyl]methyl]propanamide (2.3g, 7.64 mmol) in borane-tetrahydrofuran complex (10 mL, 1 M) was stirredat 60° C. for 1 h. The reaction was quenched by addition of methanol (10mL) and concentrated HCl (3 mL), and stirred at 60° C. for another 1 h.The mixture was concentrated under vacuum, and then diluted with water(20 mL) and extracted with ethyl acetate (20 mL×3). The combined organicphase was dried over anhydrous sodium sulfate and concentrated undervacuum. The residue was purified by silica gel column with ethylacetate/petroleum ether (1/3) as the eluent to afford the desiredproduct (1.0 g, 46% yield).

Step 4. Synthesis of 13-5

A solution of[4-(trifluoromethoxy)phenyl]methyl](3,3,3-trifluoropropyl)amine (720 mg,2.51 mmol), 1-(4-fluoro-3-nitrophenyl)cyclopentane-1-carbonitrile (590mg, 2.52 mmol) and N,N-diisopropylethylamine (0.65 g) in dimethylsufoxide (10 mL) was stirred at 130° C. for overnight. The mixture wascooled to room temperature, diluted with ethyl acetate (60 mL), andwashed with water (30 mL×2) and brine (30 mL). The organic phase wasdried over anhydrous sodium sulfate and concentrated under vacuum. Theresidue was purified by silica gel column with ethyl acetate/petroleumether (1/10) as the eluent to afford the desired product (0.47 g, 37%yield).

Step 5. Synthesis of 13-6

To a solution of1-[3-nitro-4-([[4-(trifluoromethoxy)phenyl]methyl](3,3,3-trifluoropropyl)amino)phenyl]cyclopentane-1-carbonitrile(470 mg, 0.94 mmol) in acetic acid (5 mL) was added iron (0.26 g). Themixture was then stirred at room temperature for 0.5 h. Ethyl acetate(30 mL) was added, and the mixture was filtered through Celite. Thefiltrate was concentrated under vacuum. The residue was purified bysilica gel column with ethyl acetate/petroleum ether (1/10) to affordthe desired product (0.33 g, 75% yield).

Step 6. Synthesis of 13-7

To a solution of1-[3-amino-4-([[4-(trifluoromethoxy)phenyl]methyl](3,3,3-trifluoropropyl)amino)phenyl]cyclopentane-1-carbonitrile(330 mg, 0.70 mmol) in water (1 mL) and ethanol (4 mL), was added KOH(1.12 g, 19.96 mmol). The mixture was then stirred at 100° C. forovernight. The reaction was cooled to room temperature, diluted withwater (10 mL), extracted with ethyl acetate (20 mL×2), and washed withbrine (10 mL). The organic phase was dried over anhydrous sodium sulfateand concentrated under vacuum to afford the desired product (160 mg, 47%yield).

Step 7. Synthesis of 13

To a solution of 2,4-difluoro-1-isocyanatobenzene (38 mg, 0.25 mmol) intetrahydrofuran (3 mL), was added1-[3-amino-4-([[4-(trifluoromethoxy)phenyl]methyl](3,3,3-trifluoropropyl)amino)phenyl]cyclopentane-1-carboxylicacid (80 mg, 0.16 mmol) and triethylamine (48 mg). The mixture wasstirred at room temperature for 0.5 h, followed by addition of ethylacetate (20 mL). The resulting mixture was washed with of water (10 mL)and brine (10 mL). The organic phase was dried over anhydrous sodiumsulfate and concentrated under vacuum. The residue was purified byPrep-HPLC with the following conditions: [Column: X Bridge Prep C18 OBDColumn, 30*50 mm, 5 um, 13 nm; mobile phase, Waters (0.1% FA) and ACN(60.0% ACN up to 90.0% in 8 min, hold 90.0% in 2 min); Detector, UV 254nm] to afford the desired product (47.4 mg, 45% yield) as an off-whitesolid. LCMS C₃₀H₂₇F₈N₃O₄ (ES, m/z): 646.4 [M+H]⁺; ¹HNMR (300 MHz,DMSO-d₆): δ 12.23 (brs, 1H), 9.34 (s, 1H), 8.55 (s, 1H), 8.11-8.01 (m,2H), 7.44 (d, J=8.7 Hz, 2H), 7.37-7.27 (m, 3H), 7.24-7.15 (m, 1H),7.08-7.02 (m, 1H), 6.92-6.88 (m, 1H), 4.18 (s, 2H), 3.21-3.09 (m, 2H),2.73-2.50 (m, 4H), 1.74-1.61 (m, 6H).

Example 14

Step 1. Synthesis of 14

A solution of1-[3-amino-4-([[4-(trifluoromethoxy)phenyl]methyl](3,3,3-trifluoropropyl)amino)phenyl]cyclopentane-1-carboxylicacid (80 mg, 0.16 mmol),1-isocyanato-4-methylbenzene (32 mg, 0.24 mmol)and triethylamine (48 mg) in tetrahydrofuran (3 mL) was stirred at roomtemperature for 0.5 h. Ethyl acetate (20 mL) was added and the resultingmixture was washed with water (10 mL) and brine (10 mL). The organicphase was dried over anhydrous sodium sulfate and concentrated undervacuum. The residue was purified by Prep-HPLC with the followingconditions: [Column: X Bridge Prep C18 OBD Column, 19*150 mm 5 um;mobile phase, Waters (0.1%FA) and ACN (50.0% ACN up to 80.0% in 8 min,hold 80.0% in 2 min); Detector, UV 254 nm] to afford the desired product(31.5 mg, 32% yield) as an off-white solid. LCMS (ES, m/z): 624.30[M+H]⁺; ¹HNMR (300 MHz, DMSO-d₆) : δ 9.39 (s, 1H), 8.23 (s, 1H), 8.18(d, J=2.1 Hz, 1H), 7.46-7.36 (m, 4H), 7.26 (d, J=8.1 Hz, 2H), 7.18-7.12(m, 3H), 6.90-6.87 (m, 1H), 4.17 (s, 2H), 3.13-3.08 (m, 2H), 2.50-2.45(m, 4H), 2.26 (s, 3H), 1.75-1.62 (m, 6H).

Example 15

Step 1. Synthesis of 15-1

To a solution of 2-methylpropan-1-amine (480 mg, 6.56 mmol) indichloromethane (10 mL), was added oxan-4-one (723 mg, 7.22 mmol) andacetic acid (0.05 mL).The resulting mixture was stirred at roomtemperature for 0.5 h before sodium cyanoborohydride (1.66 g, 26.42mmol) was added. After stirring at room temperature for another 3 h, themixture was quenched by the addition of a solution of ammonium chloride(50 mL), and extracted with dichloromethane (50 mL×2). The organic phasewas washed with brine (50 mL×2), dried over anhydrous sodium sulfate,and concentrated under vacuum to afford the desired product (0.80 g, 78%yield).

Step 2. Synthesis of 15-2

To a solution of 1-(4-fluoro-3-nitrophenyl)cyclopentane-1-carbonitrile(1.0 g, 4.274 mmol) in dimethyl sulfoxide (30 mL) at room temperature,were added N,N-diisopropylethylamine (1.1 g, 8.548 mmol) andN-(2-methylpropyl)oxan-4-amine (1.0 g, 6.411 mmol). The resultingsolution was stirred overnight at 130° C. The reaction was quenched byaddition of water (30 mL) and the mixture was extracted with ethylacetate (30 mL×3). The combined organic layer was washed with brine(40×3), dried over anhydrous sodium sulfate, and concentrated undervacuum. The residue was applied onto a silica gel column with ethylacetate/petroleum ether (1:25) as eluent to afford the desired product(0.30 g, 19% yield).

Step 3. Synthesis of 15-3

To a solution of1-[4-[(2-methylpropyl)(oxan-4-yl)amino]-3-nitrophenyl]cyclopentane-1-carbonitrile(0.3 g, 0.808 mmol) in methanol (10 mL) was added palladium on carbonunder N₂. The suspension was degassed under vacuum and purged with H₂several times. The resulting nixture was stirred under H₂ baloon at 25°C. overnight. The solids were filtered off and the filter cake waswashed with methanol (10 mL×3). The filtrate was concentrated undervacuum and applied onto a silica gel column with ethyl acetate/petroleumether (2:7) as eluent to afford the desired product (0.18 g, 65% yield).

Step 4. Synthesis of 15-4

To a solution of1-[3-amino-4-[(2-methylpropyl)(oxan-4-yl)amino]phenyl]cyclopentane-1-carbonitrile(0.18 g, 0.528 mmol) in ethanol (10 mL) were added potassium hydroxide(0.29 g, 5.28 mmol) and water (6 mL). The resulting solution was stirredat 130° C. for 3 days. The reaction mixture was cooled to roomtemperature with a water/ice bath. The pH value of the solution wasadjusted to 5 with hydrochloric acid (1 N) and the mixture was extractedwith ethyl acetate (20 mL×3). The combined organic layer was washed withbrine (30 mL×3), dried over anhydrous sodium sulfate, and concentratedunder vacuum to afford the desired product (0.16 g, 84% yield).

Step 5. Synthesis of 15

To a solution of 3-methyl-1,2-oxazol-5-amine (0.12 g, 1.22 mmol) indichloromethane (12 mL), were added N,N-diisopropylethylamine (0.21 g,1.663 mmol) and triphosgene (0.12 mg, 0.41 mmol) under N₂. The resultingsolution was stirred for 20 minutes at room temperature, followed by theaddition of1-[3-amino-4-[(2-methylpropyl)(oxan-4-yl)amino]phenyl]cyclopentane-1-carboxylicacid (0.11 g, 0.31 mmol, 1.00 equiv) and then triethylamine (0.19 g,1.83 mmol, 6.00 equiv). The reaction was stirred at room temperature foranother 2 hours. The reaction was quenched by addition of methanol (8mL) and water (20 mL), and the mixture was extracted withdichloromethane (20 mL×3). The combined organic layer was washed withbrine (30 mL×3), dried over anhydrous sodium sulfate, and concentratedunder vacuum. The crude product was purified by prep-HPLC [Column,Xbridge, RP18, 19*150 mm; mobile phase, A: formic acid (aq) (0.1%), B:acetonitrile (35%-75% in 8 min); rate, 25 mL/min; Detector, 254 nm] toafford the product (72.3 mg, 49% yield) as a white solid. LCMS: (ES,m/z): [M+H]+ 485.4. ¹HNMR (300 MHz, CD₃OD, ppm) δ 8.25 (d, J=2.1 Hz,1H), 7.22 (d, J=8.4 Hz, 1H), 7.09 (dd, J=2.1 Hz, J=8.4 Hz, 1H), 6.06 (s,1H), 3.94-3.89 (m, 2H), 3.31 (s, 2H), 2.92-2.83 (m, 3H), 2.65-2.61 (m,2H), 2.24 (s, 3H), 1.93-1.87 (m, 2H), 1.78 (s, 6H), 1.76-1.57 (m, 2H),1.48-1.32 (m, 1H), 0.85 (d, J=6 Hz, 6H).

Example 16

Step 1. Synthesis of 16-1

To a solution of2-[4-[bis(2-methylpropyl)amino]-3-nitrophenyl]acetonitrile (1.0 g, 3.46mmol) in tetrahydrofuran (10 mL) at 0° C., was added sodium hydride (410mg, 10.25 mmol) portionwise. At the same temperature, the mixture wasstirred for 30 min, followed byaddition of a solution of1,3-dibromopropane (840 mg, 4.16 mmol) in THF (2 mL). The resultingmixture was stirred at room temperature for another 3 h. The reactionwas then quenched byaddition of water (2 mL). The mixture was dilutedwith ethyl acetate (60 mL), and washed with water (30 mL) and brine (30mL). The organic phase was dried over anhydrous sodium sulfate andconcentrated under vacuum. The residue was purified by silica gel columnwith ethyl acetate/petroleum ether (1/10) as the eluent to afford thedesired product (0.4 g, 35% yield).

Step 2. Synthesis of 16-2

To a solution of1-[4-[bis(2-methylpropyl)amino]-3-nitrophenyl]cyclobutane-1-carbonitrile(400 mg, 1.21 mmol) in acetic acid (10 mL) was added iron (680 mg, 12.14mmol). The resulting mixture was stirred at room temperature for 1 h.The reaction was filtered through Celite and the filtrate was dilutedwith ethyl acetate (50 mL), and washed with saturated aqueous sodiumcarbonate (20 mL) and water (20 mL). The organic phase was dried overanhydrous sodium sulfate and concentrated under vacuum. The residue waspurified by silica gel column with ethyl acetate/petroleum ether (1/10)as the eluent to afford the desired product (0.198 g, 54% yield).

Step 3. Synthesis of 16-3

To a solution of1-[3-amino-4-[bis(2-methylpropyl)amino]phenyl]cyclobutane-1-carbonitrile(198 mg, 0.66 mmol) in ethanol (4 mL) and water (2 mL) at roomtemperature, was added potassium hydroxide (110 mg, 1.96 mmol). Thereaction was then stirred at 100° C. for overnight. The mixture wascooled to room temperature, diluted with water (20 mL), and extractedwith ethyl acetate (20 mL×3). The organic phase was dried over anhydroussodium sulfate and concentrated under vacuum. The residue was purifiedby silica gel column with dichloromethane/methanol (10/1) as the eluentto afford the desired product (110 mg, 52% yield).

Step 4. Synthesis of 16

To a solution of1-[3-amino-4-[bis(2-methylpropyl)amino]phenyl]cyclobutane-1-carboxylicacid (82 mg, 0.26 mmol) in tetrahydrofuran (3 mL), was addedtriethylamine (53 mg, 0.52 mmol) and 2,4-difluoro-1-isocyanatobenzene(60 mg, 0.39 mmol). The reaction was then stirred at room temperaturefor 1 h. The mixture was diluted with ethyl acetate (20 mL), and washedwith water (10 mL×2). The organic phase was concentrated under vacuum.The residue was purified by Prep-HPLC with the following conditions:[Column, X Bridge Shield RP18 OBD Column, 5 um,19*150 mm; mobile phase,water (10 mmol/L NH₄HCO₃) and ACN (15.0% ACN up to 65.0% in 8 min);Detector, UV 254; 220 nm] to afford the desired product (44.7 mg, 37%yield). LCMS (ES, m/z): 474.50 [M+H]⁺; ¹HNMR: (300 MHz, DMSO-D₆, ppm): δ9.23 (s, 1H), 8.01-7.88 (m, 2H), 7.77 (s, 1H), 7.31-7.25 (m, 1H),7.08-7.00 (m, 2H), 6.86 (d, J=6.9 Hz, 1H), 2.90-2.61 (m, 6H), 2.30-2.20(m, 2H), 1.82-1.62 (m, 4H), 0.83 (d, J=6.6 Hz, 12H).

Example 17

Step 1. Synthesis of 17

To a solution of 3-methyl-1,2-oxazol-5-amine (98.1 mg, 1.00 mmol) andN,N-diisopropylethylamine (175 mg, 1.35 mmol) in tetrahydrofuran (3 mL)at room temperature, was added a solution of ditrichloromethyl carbonate(101 mg, 0.34 mmol) in THF (3 mL). The reaction was stirred for 15 min.Triethylamine (152 mg, 1.50 mmol) and1-[3-amino-4-[bis(2-methylpropyl)amino]phenyl]cyclobutane-1-carboxylicacid (80 mg, 0.25 mmol) was added, and the resulting mixture was stirredat room temperature for another 2 h. The reaction was concentrated undervacuum. The residue was dissolved in methanol (4 mL) and purified byPrep-HPLC with the following conditions: [Column: X bridge, C18, 19*50mm; Mobile Phase, H₂O (0.05% NH4HCO3)/MeCN, 35%-55% in 8 min; Rate: 25mL/min; Detector, 254 nm] to afford the desired product (27.5 mg, 6%yield) as a white solid. LCMS (ES, m/z): 443.5 [M+H]⁺; ¹HNMR: (300 MHz,DMSO-d₆, ppm): δ 8.26 (s, 1H), 7.88 (d, J=2.1 Hz, 1H), 7.17 (d, J=8.3Hz, 1H), 6.91 (dd, J=8.2, 2.2 Hz, 1H), 5.99 (s, 1H), 2.75-2.60 (m, 6H),2.40-2.25 (m, 2H), 2.16 (s, 3H), 1.91-1.80 (m, 1H), 1.77-1.70 (m, 1H),1.68-1.55 (m, 2H), 0.82 (d, J=6.5 Hz, 12H).

Example 18

Step 1. Synthesis of 18

To a solution of pyrimidin-5-amine (95.1 mg, 1.00 mmol) andN,N-diisopropylethylamine (175 mg, 1.35 mmol) in tetrahydrofuran (3 mL)at room temperature, was added a solution of ditrichloromethyl carbonate(101 mg, 0.34 mmol) in THF (3 mL) dropwise. After stirring for 15 min,triethylamine (152 mg, 1.50 mmol) and1-[3-amino-4-[bis(2-methylpropyl)amino]phenyl]cyclobutane-1-carboxylicacid (80 mg, 0.25 mmol) was added. The resulting mixture was stirred atroom temperature for another 2 h. The reaction was then concentratedunder vacuum. The residue was purified by Prep-HPLC with the followingconditions: [Column: X bridge, C18, 19*50 mm; Mobile Phase, H₂O (0.05%NH₄HCO₃)/MeCN, 35%-55% in 8 min; Rate: 25 mL/min; Detector, 254 nm] toafford the desired product (72.7 mg, 17% yield) of as a white solid.LCMS (ES, m/z): 440.5 [M+H]⁺. ¹HNMR (300 MHz, DMSO-d₆, ppm): δ 10.01 (s,1H), 8.93 (s, 2H), 8.81 (s, 1H), 8.20 (s, 1H), 7.90 (d, J=2.1 Hz, 1H),7.19 (d, J=8.3 Hz, 1H), 6.92 (dd, J=8.3, 2.2 Hz, 1H), 2.68 (d, J=6.9 Hz,6H), 2.42-2.26 (m, 2H), 1.94-1.50 (m, 4H), 0.86 (d, J=6.5 Hz, 12H).

Example 19

Step 1. Synthesis of 19-1

To a solution of1-[3-amino-4-[bis(2-methylpropyl)amino]phenyl]cyclobutane-1-carbonitrile(270 mg, 0.90 mmol) in tetrahydrofuran (5 mL), was added2,4-difluoro-1-isocyanatobenzene (210 mg, 1.35 mmol) and triethylamine(182 mg, 1.80 mmol). The mixture was then stirred at room temperaturefor 2 h. The reaction was diluted with ethyl acetate (20 mL), and washedwith water (10 mL) and brine (10 mL). The organic phase was dried overanhydrous sodium sulfate and concentrated under vacuum. The residue wasby silica gel column with ethyl acetate/petroleum ether (1/1) as theeluent to afford the desired product (230 mg, 56% yield).

Step 2. Synthesis of 19

A solution of3-[2-[bis(2-methylpropyl)amino]-5-(1-cyanocyclobutyl)phenyl]-1-(2,4-difluorophenyl)urea(120 mg, 0.26 mmol), trimethylsilyl azide (152 mg, 1.32 mmol), andtetrabutylammonium fluoride (345 mg, 1.32 mmol) was stirred at 90° C.for 1 h. The mixture was cooled to room temperature, diluted with ethylacetate (10 mL), and washed with water (10 mL×2). The organic phase wasconcentrated under vacuum. The residue was purified by silica gel columnwith ethyl acetate/petroleum ether (5/1) as the eluent to afford thedesired product (43.4 mg, 33% yield) as a white solid. LCMS (ES, m/z):498.5[M+H]⁺. ¹HNMR: (300 MHz, DMSO-d₆, ppm): δ 9.28 (s, 1H), 8.03 (s,1H), 7.82-7.81 (m, 1H), 7.80 (s, 1H), 7.29 (m, 2H), 7.14-7.12 (m, 1H),6.87 (m, 1H), 2.81-2.79 (m, 2H), 2.65-2.62 (m, 6H), 1.89 (m, 2H),1.63-1.61 (m, 2H), 0.83 (d, J=6.6 Hz, 12H).

Example 20

Step 1. Synthesis of 20-2

To a solution of 2-(4-fluorophenyl)acetonitrile (20 g, 148.00 mmol) intetrahydrofuran (200 mL) at 0° C., was added sodium hydride (10.66 g,444.17 mmol) portionwise. The mixture was stirred at 0° C. for 30 min,followed by the addition of 1,3-dibromopropane (32.58 g, 161.38 mmol).The resulting mixture was stirred at room temperature for overnight. Thereaction was quenched with saturated ammonium chloride (50 mL), andextracted with ethyl acetate (300 mL×3). The organic phase was washedwith brine (300 mL×2), dried over anhydrous sodium sulfate, andconcentrated under vacuum. The residue was purified by silica gel columnwith ethyl acetate/petroleum ether (1/20) as the eluent to afford thedesired product (13.6 g, 52% yield).

Step 2. Synthesis of 20-3

To a solution of 1-(4-fluorophenyl)cyclobutane-1-carbonitrile (13.6 g,77.6 mmol) in sulfuric acid (136 mL) at 0° C., was added potassiumnitrate (11.6 g, 114.7 mmol) in portions. The reaction was then stirredat room temperature for overnight. The reaction was quenched with water(500 mL), and extracted with ethyl acetate (300 mL×3). The organic phasewas washed with brine (200 mL×2), dried over anhydrous sodium sulfate,and concentrated under vacuum. The residue was purified by silica gelcolumn with ethyl acetate/petroleum ether (2/3) as the eluent to affordthe desired product (12.6 g, 39% yield).

Step 3. Synthesis of 20-4

To a solution of 1-(4-fluoro-3-nitrophenyl)cyclobutane-1-carboxamide(12.6 g, 52.89 mmol) in 1,4-dioxne (126 mL), was added trifluoroaceticanhydride (16 mL) and triethylamine (6.7 mL). The resulting mixture wasthen heated to 100° C. for overnight. The reaction was cooled to roomtemperature, diluted with water (100 mL), and extracted with ethylacetate (160 mL×3). The organic phase was washed with brine (100 mL×5),dried over anhydrous sodium sulfate, and concentrated under vacuum. Theresidue was purified by silica gel column with ethyl acetate/petroleumether (1/9) as the eluent to afford the desired product (10.5 g, 90%yield).

Step 4. Synthesis of 20-6

To a solution of 1-(4-fluoro-3-nitrophenyl)cyclobutane-1-carbonitrile(600 mg, 2.72 mmol) and N-ethylcyclohexanamine (416 mg, 3.27 mmol) indimethyl sufoxide (6 mL), was added N,N-diisopropylethylamine (1057.1mg, 8.18 mmol). The resulting mixture was stirred at 100° C. forovernight. The reaction was cooled to room temperature, diluted withethyl acetate (100 mL), and washed with water (100 mL×2) and brine (100mL). The organic phase was dried over anhydrous sodium sulfate andconcentrated under vacuum. The residue was purified by Flash-Prep-HPLCwith the following conditions (IntelFlash-1): [Column: silica gelcolumn; Mobile Phase: methanol/dichloromethane from 0% increasing to 8%within 20 min; Detector, UV 254 nm] to afford the desired product (700mg, 78% yield).

Step 5. Synthesis of 20-7

To a solution of1-[4-[cyclohexyl(ethyl)amino]-3-nitrophenyl]cyclobutane-1-carbonitrile(700 mg, 2.14 mmol) in acetic acid (7 mL), was added iron (2.39 g, 42.79mmol). The mixture was stirred at room temperature for 30 min beforewater (100 mL) was added. The pH value of the mixture was adjusted to 9with aqueous sodium carbonate. The solid was filtered off and thefiltrate was extracted with ethyl acetate (100 mL×3), and washed withbrine (200 mL). The organic phase was dried over anhydrous sodiumsulfate and concentrated under vacuum to afford the desired product (600mg, 94% yield).

Step 6. Synthesis of 20-8

To a solution of1-[3-amino-4-[cyclohexyl(ethyl)amino]phenyl]cyclobutane-1-carbonitrile(550 mg, 1.85 mmol) in ethanol (9 mL) and water (3 mL), was addedpotassium hydroxide (1.56 g, 27.76 mmol). The resulting mixture wasstirred at 100° C. for 23 h. The reaction was cooled to room temperatureand diluted with water (100 mL). The pH value of the mixture wasadjusted to 4 with hydrogen chloride (1 N), and then extracted withethyl acetate (100 mL×3). The organic phase was washed with brine (100mL), dried over anhydrous sodium sulfate, and concentrated under vacuumto afford the desired product (450 mg, 77% yield).

Step 7. Synthesis of 20

To a solution of1-[3-amino-4-[cyclohexyl(ethyl)amino]phenyl]cyclobutane-1-carboxylicacid (210 mg, 0.66 mmol) and 2,4-difluoro-1-isocyanatobenzene (154.7 mg,1.00 mmol) in tetrahydrofuran (5 mL), was added triethylamine (200.9 mg,1.99 mmol). The reaction was stirred at room temperature for 2.5 hbefore ethyl acetate (50 mL) was added. The mixture was washed withwater (50 mL×2) and brine (50 mL), and the organic phase was dried overanhydrous sodium sulfate and concentrated under vacuum. The residue waspurified by Prep-HPLC with the following conditions: [Column, X BridgePrep C18 OBD Column, 19*150 mm 5 um; mobile phase, water (10 mmol/LNH₄HCO₃)/CH₃CN; MeCN from 25.0% to 55.0% in 8 min; Detector, UV 245 nm]to afford the desired product (80.4 mg, 26% yield) as a white solid.LCMS (ES, m/z): 472.5 [M+H]⁺; ¹HNMR: (300 MHz, DMSO-d₆, ppm) : δ9.39 (s,1H), 8.74 (s, 1H), 8.19-7.94 (m, 2H), 7.33-7.26 (m, 1H), 7.22-6.97 (m,2H), 6.91-6.81 (m, 1H), 3.00 (q, J=7.0 Hz, 2H), 2.75-2.60 (m, 3H),2.42-2.25 (m, 2H), 1.97-1.53 (m, 7H), 1.20-1.00 (m, 5H), 0.82 (t, J=7.0Hz, 3H).

Example 21

Step 1. Synthesis of 21-1

To a solution of 1-(4-fluoro-3-nitrophenyl)cyclobutane-1-carbonitrile (1g, 4.54 mmol) in dimethyl sulfoxide (10 mL), were addedN,N-diisopropylethylamine (1.76 g, 13.62 mmol) and thenN-(2-methylpropyl)cyclohexanamine (777 mg, 5.00 mmol). The mixture wasstirred at 100° C. for 16 h. After cooling to room temperature, themixture was concentrated under vacuum. The residue was purified byFlash-Prep-HPLC with the following conditions: [Column: C18 silica gel;mobile phase A: water (0.05% TFA)), Mobile phase B: CAN; Gradient: 45%to 100% ACN; Detector: UV 254 nm] to afford the desired product (0.8 g,50% yield).

Step 2. Synthesis of 21-2

To a solution of1-[4-[cyclohexyl(2-methylpropyl)amino]-3-nitrophenyl]cyclobutane-1-carbonitrile(800 mg, 2.25 mmol) in ethyl acetate (5 mL) and acetic acid (5 mL) wasadded iron (1.26 g, 22.56 mmol). The reaction was then stirred at roomtemperature for 0.5 h. The mixture was diluted with ethyl acetate (1500mL), and the solid was filtered off. The pH value of the filtrate wasadjusted to 9 with sodium carbonate. The organic phase was washed withbrine (50 mL×2), dried over anhydrous sodium sulfate, and concentratedunder vacuum. The residue was purified by silica gel column with ethylacetate/petroleum ether (1/6) as the eluent to afford the desiredproduct (0.5 g, 68% yield).

Step 3. Synthesis of 21-3

To a solution of1-[3-amino-4-[cyclohexyl(2-methylpropyl)amino]phenyl]cyclobutane-1-carbonitrile(300 mg, 0.92 mmol) in ethanol (6 mL) and water(1.5 mL) was addedpotassium hydroxide (900 mg, 16.04 mmol). The reaction was then stirredat 95° C. for 16 h. After cooling to room temperature, the mixture wasconcentrated under vacuum and the residue was dissolved in water (50mL). The pH value of the mixture was adjusted to 4 with hydrogenchloride (1 N). The mixture was extracted with ethyl acetate (50 mL×2),and washed with saturation brine (50 mL×2). The organic phase was driedover anhydrous sodium sulfate and concentrated under vacuum to affordthe desired product (0.3 g, 94% yield).

Step 4. Synthesis of 21

To a solution of1-[3-amino-4-[cyclohexyl(2-methylpropyl)amino]phenyl]cyclobutane-1-carboxylicacid (300 mg, 0.87 mmol) in tetrahydrofuran (6 mL) were addedtriethylamine (264 mg, 2.61 mmol) and 2,4-difluoro-1-isocyanatobenzene(149 mg, 0.96 mmol). The reaction was then stirred at room temperaturefor 1.5 h. The mixture was concentrated under vacuum and the residue waspurified by Prep-HPLC with the following conditions: [Column: WatersX-bridge C18, 5 um, 19×150 mm; Mobile phase A: water (0.05% NH₄HCO₃),Mobile phase B: CAN; Gradient: 25% CAN to 50% ACN in 8 min; Detector: UV254 nm] to afford the desired product (62.5 mg, 14% yield) as a whitesolid. LCMS: (ES, m/z): 500.30 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆, ppm): δ9.31 (s, 1H), 8.09 (s, 1H), 7.87-7.79 (m, 2H), 7.27-7.21 (m, 1H),7.05-6.95 (m, 2H), 6.81-6.78 (m, 1H), 2.83-2.52 (m, 4H), 2.28-2.12 (m,2H), 1.93-1.53 (m, 6H), 1.52-1.38 (m, 1H), 1.37-0.86 (m, 6H), 0.75 (d,J=6.5 Hz, 6H).

Example 22

Step 1. Synthesis of 22-1

To a solution of 1-(4-fluoro-3-nitrophenyl)cyclobutane-1-carbonitrile (1g, 4.54 mmol) in dimethyl sufoxide (10 mL), was addedN-(2-methoxyethyl)cyclohexanamine (1.16 g, 7.38 mmol) andN,N-diisopropylethylamine (1.74 g). The mixture was then stirred at 100°C. for overnight. The reaction was cooled to room temperature, quenchedby addition of water (50 mL), and extracted with ethyl acetate (300mL×3). The organic phase was dried over anhydrous sodium sulfate andconcentrated under vacuum to afford the desired product (0.7 g, 43%yield).

Followed similar steps 2-4 in example 21 to synthesize 22

Example 22: LCMS (ES, m/z): 502.4 [M+H]⁺; ¹HNMR (300 MHz, DMSO-d₆): δ9.34 (s, 1H), 8.61 (s, 1H), 8.06 (d, J=1.8 Hz, 1H), 8.01-7.93 (m, 1H),7.33-7.26 (m, 1H), 7.16 (d, J=8.1 Hz, 1H), 7.06-7.00 (m, 1H), 6.87-6.84(m, 1H), 3.24-3.07 (m, 7H), 2.78-2.62 (m, 3H), 2.31-2.26 (m , 2H),1.89-1.66 (m, 6H), 1.53-1.49 (m, 1H), 1.23-1.00 (m, 4H).

Example 23

Step 1. Synthesis of 23-1

To a solution of 1-(4-fluoro-3-nitrophenyl)cyclobutane-1-carbonitrile(500 mg, 2.27 mmol) in dimethyl sulfoxide (10 mL), was added2-methyl-1-[(2-methylpropyl)amino]propan-2-ol (330 mg, 2.27 mmol) andN,N-diisopropylethylamine (354 mg, 2.72 mmol). The resulting mixture wasstirred at 100° C. for 12 h. After cooling to room temperature, themixture was diluted with water (50 mL), and extracted with ethyl acetate(50 mL×3). The organic was washed with brine (50 mL), dried overanhydrous sodium sulfate, and concentrated under vacuum to afford thedesired product (350 mg, 45%).

Followed similar steps 2-4 in example 21 to synthesize 23

Example 23: LCMS (ES, m/z): 490.3 [M+H]⁺; ¹HNMR (300 MHz, CD₃OD, ppm):δ7.98 (s, 1H), 7.93-7.85 (m, 1H), 7.25 (d, J=8.4 Hz, 1H), 7.05-6.90 (m,3H), 3.02 (s, 2H), 2.87 (d, J=6.9 Hz, 2H), 2.82-2.74 (m, 2H), 2.52-2.42(m, 2H), 2.01-1.92 (m, 1H), 1.92-1.83 (m, 1H), 1.60-1.55 (m, 1H), 1.14(s, 6H), 0.87 (d, J=6.6 Hz, 6H).

Example 24

Step 1. Synthesis of 24-1

To a solution of 1-(4-fluoro-3-nitrophenyl)cyclobutane-1-carbonitrile(500 mg, 2.27 mmol) in dimethyl sufoxide (6 mL), was addedN-ethyloxan-4-amine (350 mg, 2.71 mmol) and N,N-diisopropylethylamine(870 mg). The resulting mixture was then stirred at 100° C. forovernight. The reaction was cooled to room temperature, diluted withwater (10 mL), and extracted with ethyl acetate (30 mL×3). The organicphase was washed with brine (30 mL×5), dried over anhydrous sodiumsulfate, and concentrated under vacuum. The residue was purified bysilica gel column with ethyl acetate/petroleum ether (3/2) as the eluentto afford the desired product (480 mg, 64% yield).

Followed similar steps 2-4 in example 21 to synthesize 24.

Example 24: LCMS (ES, m/z): 474.3 [M+H]⁺; ¹H NMR (300 MHz, DMSO-d₆,ppm): δ 9.42 (s, 1H), 8.80 (s, 1H), 8.14-8.13 (d, J=2.1 Hz, 1H),8.07-7.99 (m, 1H), 7.34-7.26 (m ,1H), 7.17 (d, J=8.2 Hz, 1H), 7.06-7.00(m, 1H), 6.87 (dd, J=8.1, 2.1 Hz, 1H), 3.84-3.81 (m, 2H), 3.27-3.23 (m,2H), 3.19-2.95 (m, 3H), 2.72-2.63 (d, J=4.5 Hz, 2H), 2.39-2.29 (m, 2H),1.97-1.69 (m, 4H), 1.42-1.37 (m, 2H), 0.84-0.79 (m, 3H).

Example 25

Step 1. Synthesis of 25-1

A solution of 1-(4-fluoro-3-nitrophenyl)cyclobutane-1-carbonitrile (1 g,4.54 mmol), N-(2-methylpropyl)oxan-4-amine (1.43 g, 9.09 mmol), andN,N-diisopropylethylamine (2.34 g, 18.11 mmol) in DMSO (20 mL) wasstirred at 100° C. for 16 h. The mixture was then cooled to roomtemperature, diluted with water (200 mL), and extracted with ethylacetate (100 mL×2). The organic phase was washed with water (100 mL×5)and brine (30 mL×2), dried over anhydrous sodium sulfate, andconcentrated under vacuum. The residue was purified by silica gel columnwith ethyl acetate/petroleum ether (1/10) as eluent to afford thedesired product (0.4 g, 19% yield).

Followed similar steps 2-4 in example 21 to synthesize 25.

Example 25: LCMS (ES, m/z): 502.4 [M+H]⁺; ¹HNMR: (300 MHz, DMSO-d₆,ppm): δ 11.8 (brs, 1H), 9.42 (s, 1H), 8.38 (s, 1H), 8.02 (d, J=1.8, 1H), 8.00-7.82 (m, 1H), 7.34-7.30 (m, 1H), 7.29-7.16 (m, 1H), 7.10-6.90(m, 1H), 6.93-6.80 (m, 1H), 3.85-3.81 (m, 2H), 3.25-3.15 (m, 2H),2.95-2.59 (m, 5H), 2.42-2.12 (m, 2H), 2.00-1.62 (m, 4H), 1.61-1.37 (m,2H), 1.36-1.17 (m, 1H), 0.82 (d, J=6.6 Hz, 6H).

Example 26

Step 1. Synthesis of 26-1

To a solution of thian-4-one (4.77 g, 41.06 mmol) and2-methylpropan-1-amine (2 g, 27.35 mmol) in dichloromethane (60 mL) wasadded acetic acid (0.1 mL). The reaction was then stirred at roomtemperature for 0.5 h. Sodium cyanoborohydride (6.87 g, 109.33 mmol) wasadded and then the reaction was stirred at room temperature for 16 h.The mixture was diluted with ethyl acetate (200 mL), washed with brine(30 mL×2), dried over anhydrous sodium sulfate, and concentrated undervacuum. The residue was purified by silica gel column with ethylacetate/petroleum ether (1/7) as the eluent to afford the desiredproduct (1.4 g, 30% yield).

Step 2. Synthesis of 26-2

To a solution of 1-(4-fluoro-3-nitrophenyl)cyclobutane-1-carbonitrile(1.04 g, 4.72 mmol) and N-(2-methylpropyl)thian-4-amine (750 mg, 4.33mmol) in dimethyl sulfoxide (10 mL) was added N,N-diisopropylethylamine(835 mg, 6.46 mmol). The reaction was then stirred at 100° C. for 2days. The mixture was cooled to room temperature and diluted with water(100 mL). The mixture was extracted with ethyl acetate (100 mL×2), andwashed with water (100 mL×3) and brine (100 mL). The organic phase wasdried over anhydrous sodium sulfate and concentrated under vacuum. Theresidue was purified by Flash-Prep-HPLC with the following conditions:[Column: C18 silica gel; Mobile phase A: water (0.05% TFA), Mobile phaseB: CAN; Gradient: 55% Can to 95% ACN; Detector: UV 254 nm] to afford thedesired product (370 mg, 21% yield).

Step 3. Synthesis of 26-3

To a solution of1-[4-[(2-methylpropyl)(thian-4-yl)amino]-3-nitrophenyl]cyclobutane-1-carbonitrile(340 mg, 0.91 mmol) in dichloromethane (10 mL) at 0° C., was added3-chlorobenzene-1-carboperoxoic acid (240 mg, 1.39 mmol). The mixturewas then stirred at 0° C. for 0.5 h and at room temperature for another1.5 h. The solid was filtered off and the filtrate was concentratedunder vacuum. The residue was purified by silica gel column with ethylacetate/petroleum ether (1/2) as the eluent to afford the desiredproduct (380 mg, crude).

Step 4. Synthesis of 26-4

To a mixture of 26-3 (330 mg, 0.81 mmol) in ethyl acetate (8 mL) andmethanol (8 mL) was added nickel (200 mg, 3.41 mmol). The suspension wasdegassed under vacuum and purged with H₂ three times. The mixture wasstirred under H₂ balloon at room temperature for 30 min. The solid wasfiltered off and the filtrate was concentrated under vacuum to affordthe desired product (265 mg, 87% yield).

Step 5. Synthesis of 26-5

To a solution of 26-4 (265 mg, 0.71 mmol) in ethanol (6 mL) and water(1.5 mL) was added sodium hydroxide (1.2 g, 30.00 mmol). The mixture wasthen stirred at 90° C. for 16 h. The reaction was cooled to roomtemperature and diluted with ethyl acetate (100 mL) and water (100 mL).The pH value of the mixture was adjusted to 4 with hydrogen chloride (1N). The mixture was extracted with ethyl acetate (100 mL×2), and washedwith brine (100 mL×2). The organic phase was dried over anhydrous sodiumsulfate and concentrated under vacuum to afford the desired product (180mg, 65% yield).

Step 6. Synthesis of 26

To a solution of 26-4 (180 mg, 0.46 mmol) in tetrahydrofuran (5 mL),were added 2,4-difluoro-1-isocyanatobenzene (78 mg, 0.50 mmol) andtriethylamine (69 mg, 0.68 mmol) sequentially. The mixture was thenstirred at room temperature for 2 h. The mixture was concentrated undervacuum and the residue was purified by Prep-HPLC with the followingconditions: [Column: X bridge, C18, 5 um, 19×150 mm; Mobile phase A:water (0.05% NH₄HCO₃), Mobile phase B: ACN; Gradient: 35% ACN to 60% ACNin 8 min; Detector: UV 254 nm] to afford the desired product (92.2 mg,37% yield) as a white solid. LCMS: (ES, m/z): 550.1 [M+H]⁺. ¹H-NMR: (300MHz, DMSO-d₆, ppm): δ 9.44 (s, 1H), 8.21 (s, 1H), 8.05 (s, 1H),7.99-7.91 (m, 1H), 7.35-7.27 (m, 1H), 7.16 (d, J=8.1 Hz, 1H), 7.11-6.98(m, 1H), 6.89-6.85 (m, 1H), 3.25-3.10 (m, 2H), 3.09-2.92 (m, 4H),2.84-2.60 (m, 4H), 2.39-2.19 (m, 4H), 2.02-1.82 (m, 2H),1.81-1.68 (m,1H), 1.41-1.21 (m, 1H), 0.83 (d, J=6.6 Hz, 6H).

Example 27

Step 1. Synthesis of 27-1

To a solution of1-[4-[(2-methylpropyl)(oxan-4-yl)amino]-3-nitrophenyl]cyclobutane-1-carbonitrile(250 mg, 0.70 mmol) in acetic acid (2.5 mL), was added iron (392 mg).The resulting solution was stirred at room temperature for 0.5 h. Thereaction was diluted with ethyl acetate (50 mL) and water (50 mL), andthe pH value of the mixture was adjusted to 9 with aqueous sodiumcarbonate. The solid was filtered off and the filtrate was extractedwith ethyl acetate (50 mL×2). The organic phase was washed with brine(50 mL×2) and water (60 mL×2), dried over anhydrous sodium sulfate, andconcentrated under vacuum. The residue was purified by silica gel columnwith ethyl acetate/petroleum ether (1/2) as the eluent to afford thedesired product (80 mg, 35% yield).

Step 2. Synthesis of 27-2

To a solution of1-[3-amino-4-[(2-methylpropyl)(oxan-4-yl)amino]phenyl]cyclobutane-1-carbonitrile(80 mg, 0.24 mmol) in ethanol (3 mL) and water (1 mL), was addedpotassium hydroxide (449 mg, 8.00 mmol). The resulting solution wasstirred at 95° C. for 16 h. After cooling to room temperature, themixture was concentrated under vacuum. The residue was dissolved inwater (50 mL), and the pH value of the solution was adjusted to 4 withhydrogen chloride (1 N). The resulting mixture was extracted with ethylacetate (50 mL×2). The organic phase was washed with brine (50 mL×2),dried over anhydrous sodium sulfate, and concentrated under vacuum toafford the desired product (70 mg, 83% yield).

Step 3. Synthesis of 27

To a solution of 3-methyl-1,2-oxazol-5-amine (57 mg, 0.58 mmol) intetrahydrofuran (1.5 mL), were added N,N-diisopropylethylamine (101 mg,0.78 mmol) and then a solution of ditrichloromethyl carbonate (58 mg,0.20 mmol) in tetrahydrofuran (1.5 mL). The resulting solution wasstirred at room temperature for 10 min. A solution of1-[3-amino-4-[(2-methylpropyl)(oxan-4-yl)amino]phenyl]cyclobutane-1-carboxylicacid (70 mg, 0.20 mmol) in tetrahydrofuran (1.5 mL) and triethylamine(87 mg, 0.86 mmol) were added, the reaction was stirred at roomtemperature for another 1 h. The resulting solution was thenconcentrated under vacuum and the residue was purified byFlash-Prep-HPLC with the following conditions [Column: C18 silica gel;Mobile phase A: ACN, Mobile phase B: water (0.05% FA)/; Gradient: 28%ACN to 55% ACN in 8 min; Detector, UV 254 nm] to afford the desiredproduct (10.5 mg) as a white solid. LCMS (ES, m/z): 471.3 [M+H]⁺. ¹HNMR:(300 MHz, DMSO-d₆, ppm): δ 11.28 (s, 1H), 8.51 (s, 1H), 8.10 (s, 1H),8.23 (d, J=8.1 Hz, 1H), 6.92 (dd, J=2.1, 8.1 Hz, 1H), 6.00 (s, 1H),3.90-3.78 (m, 2H), 3.24-3.16 (m, 2H), 2.86-2.62 (m, 5H), 2.43-2.30 (m,2H), 2.21-2.13 (m, 3H), 2.00-2.66 (m, 4H), 1.60-1.47 (m, 2H), 1.37-1.21(m, 1H), 0.82 (d, J=6.0 Hz, 6H).

Example 28

Step 1. Synthesis of 28-1

To a solution of 1-methylpiperidin-4-one (3.06 g, 27.07 mmol) and2-methylpropan-1-amine (1.8 g, 24.61 mmol) in dichloromethane (40 mL) at0° C., was added acetic acid (0.1 mL, cat.). Sodium cyanoborohydride(6.2 g, 98.51 mmol, 4.00 equiv) was added, and the reaction was thenstirred at room temperature for 2.5 h. The reaction mixture was dilutedwith ethyl acetate (400 mL), and washed with water (400 mL×2) and brine(400 mL). The organic phase was dried over anhydrous sodium sulfate andconcentrated under vacuum. The residue was dissolved in methanol (3 mL),and a solution of oxalic acid dihydrate (2.2 g) in methanol (10 mL) wasadded. The solids were collected by filtration and re-dissolved in water(50 mL). The pH value of the solution was adjusted to 9 with aqueoussodium hydroxide (15%). The resulting mixture was extracted withdichloromethane (400 mL×4). The organic phase was dried over anhydroussodium sulfate and concentrated under vacuum to afford the desiredproduct (650 mg, 16% yield)

Step 2. Synthesis of 28-2

To a solution of 1-methyl-N-(2-methylpropyl)piperidin-4-amine (441.4 mg,2.59 mmol) and 1-(4-fluoro-3-nitrophenyl)cyclobutane-1-carbonitrile (474mg, 2.15 mmol) in dimethyl sulfoxide (6 mL) was addedN,N-diisopropylethylamine (883.1 mg, 6.83 mmol). The reaction was thenstirred at 100° C. for 16 h. The reaction mixture was cooled to roomtemperature and diluted with ethyl acetate (100 mL). The mixture waswashed with water (100 mL×2) and brine (100 mL). The organic phase wasdried over anhydrous sodium sulfate and concentrated under vacuum. Theresidue was purified by Flash-Prep-HPLC with the following conditions:[Column: silica gel; Mobile phase A: dichloromethane, Mobile phase B:methanol; Gradient: 0% methanol to 8% methanol in 20 min; Detector: UV254 nm] to afford the desired product (600 mg, 75% yield).

Followed similar steps 2-4 in example 21 to synthesize 28.

Example 28: LRMS: (ES, m/z): 515.3 [M+H]⁺. ¹HNMR (300 MHz, DMSO-d₆,ppm): δ 9.41 (s, 1H), 8.31 (s, 1H), 7.97-7.88 (m, 2H), 7.34-7.26 (m,1H), 7.15 (d, J=8.1 Hz, 1H), 7.07-7.04 (m, 1H), 6.87 (dd, J=8.1, 2.4 Hz,1H), 2.77-2.63 (m, 5H), 2.39-2.27 (m, 2H), 2.08 (s, 3H), 1.87-1.73 (m,6H), 1.52-1.21 (m, 5H), 0.82 (d, J=6.6 Hz, 6H).

Example 29

Step 1. Synthesis of 29-2

To a solution of 2-(4-fluorophenyl)acetonitrile (1.35 g, 9.99 mmol) intetrahydrofuran (10 mL) at −78° C., was added MeLi (10 mL, 1 M)dropwise. The resulting mixture was stirred at the same temperature for30 min, and followed by addition of 2-(bromomethyl)oxirane (1.37 g,10.00 mmol) and methylmagnesiumiodide (4 mL) sequentially. The resultingmixture was allowed to warm to room temperature and stirred for another12 h. The reaction was quenched by addition of water/ice (200 mL), andextracted with ethyl acetate (50 mL×3). The organic phase was dried overanhydrous sodium sulfate, and concentrated under vacuum. The residue waspurified by silica gel column with ethyl acetate/petroleum ether (1/20)as the eluent to afford the desired product (1.3 g, 68% yield).

Step 2. Synthesis of 29-3

To a solution of 1-(4-fluorophenyl)-3-hydroxycyclobutane-1-carbonitrile(750 mg, 3.92 mmol) in dichloromethane (10 mL) at 0° C., was addedDess-Martin periodinane (2.5 g, 0.01 mmol) in portions. The resultingmixture was then stirred at room temperature for 12 h before quenched byaddition of water/ice (100 mL). The solid was filtered off, and washedwith dichloromethane (50 mL×2). The filtrate was then extracted withdichloromethane (50 mL×2). The organic phase was dried over anhydroussodium sulfate, and concentrated under vacuum. The residue was purifiedby silica gel column with ethyl acetate/petroleum ether (1/20) as theeluent to afford the desired product (550 mg, 74% yield).

Step 3. Synthesis of 29-4

To a solution of 1-(4-fluorophenyl)-3-oxocyclobutane-1-carbonitrile (210mg, 1.11 mmol) in dichloromethane (2 mL) at 0° C., was addeddiethylaminosulfur trifluoride (563 mg, 3.49 mmol) dropwise. The mixturewas then stirred at room temperature for 12 h. The reaction was quenchedby addition of water/ice (20 mL), extracted with ethyl acetate (10mL×3), and washed with brine (60 mL). The organic phase was dried overanhydrous sodium sulfate and concentrated under vacuum. The residue waspurified by silica gel column with ethyl acetate/petroleum ether (1/10)as the eluent to afford the desired product (160 mg, 68% yield).

Step 4. Synthesis of 29-5

To a solution of3,3-difluoro-1-(4-fluorophenyl)cyclobutane-1-carbonitrile (160 mg, 0.76mmol) in concentrated sulfuric acid (2 mL) at 0° C., was added potassiumnitrate (92 mg) in portions. The mixture was then stirred at roomtemperature for 12 h. The reaction was quenched by the addition ofwater/ice (20 mL), extracted with ethyl acetate (20 mL×3), and washedwith brine (60 mL). The organic phase was dried over anhydrous sodiumsulfate and concentrated under vacuum. The residue was purified bysilica gel column with ethyl acetate/petroleum ether (1/30) as theeluent to afford the desired product (150 mg, 72% yield).

Step 5. Synthesis of 29-6

To a solution of3,3-difluoro-1-(4-fluoro-3-nitrophenyl)cyclobutane-1-carboxamide (150mg, 0.55 mmol) in 1,4-dioxane (5 mL), was added trifluoroaceticanhydride (0.5 mL) and triethylamine (1.1 mL). The resulting mixture wasthe stirred at 120° C. for 12 h. The reaction was cooled to roomtemperature, quenched by the addition of water/ice (20 mL), extractedwith ethyl acetate (20 mL×3), and washed with brine (60 mL). The organicphase was dried over anhydrous sodium sulfate and concentrated undervacuum. The residue was purified by silica gel column with ethylacetate/petroleum ether (1/20) as the eluent to afford the desiredproduct (100 mg, 71% yield).

Step 6. Synthesis of 29-7

To a solution of3,3-difluoro-1-(4-fluoro-3-nitrophenyl)cyclobutane-1-carbonitrile (100mg, 0.39 mmol, 1.00 equiv) and N,N-diisopropylethylamine (76 mg, 0.59mmol) in dimethyl sufoxide (2 mL), was added bis(2-methylpropyl)amine(60 mg, 0.46 mmol). The mixture was then stirred at 90° C. for 12 h. Thereaction was cooled to room temperature, quenched by addition ofwater/ice (50 mL), extracted with ethyl acetate (50 mL×3), and washedwith brine (20 mL). The organic phase was dried over anhydrous sodiumsulfate and concentrated under vacuum. The residue was purified bysilica gel column with ethyl acetate/petroleum ether (1/20) as theeluent to afford the desired product (60 mg, 42% yield).

Step 7. Synthesis of 29-8

To a solution of3,3-difluoro-1-(4-fluoro-3-nitrophenyl)cyclobutane-1-carbonitrile (100mg, 0.39 mmol) and N,N-diisopropylethylamine (76 mg, 0.59 mmol) indimethyl sufoxide (2 mL), was added bis(2-methylpropyl)amine (60 mg,0.46 mmol). The resulting mixture was then stirred at 90° C. for 12 h.The reaction was cooled to room temperature, quenched by the addition ofwater/ice (50 mL), extracted with ethyl acetate (50 mL×3), and washedwith brine (20 mL). The organic phase was dried over anhydrous sodiumsulfate and concentrated under vacuum. The residue was purified bysilica gel column with ethyl acetate/petroleum ether (1/20) as theeluent to afford the desired product (60 mg, 42% yield).

Step 8. Synthesis of 29-9

To a solution of1-[3-amino-4-[bis(2-methylpropyl)amino]phenyl]-3,3-difluorocyclobutane-1-carbonitrile(40 mg, 0.12 mmol) in ethanol (2 mL) and water (1 mL), was addedpotassium hydroxide (10 mg, 0.18 mmol). The resulting mixture was thenstirred at room temperature for 36 h. Water (10 mL) was added, themixture was extracted with ethyl acetate (10 mL×2). The combined organicphase was washed with brine (10 mL×3), dried over anhydrous sodiumsulfate and concentrated under vacuum. The residue was purified byPre-TLC with ethyl acetate/petroleum ether (1/10) to afford the desiredproduct (40 mg, 88% yield).

Step 9. Synthesis of 29

To a solution of1-[3-amino-4-[bis(2-methylpropyl)amino]phenyl]-3,3-difluorocyclobutane-1-carboxylicacid (40 mg, 0.11 mmol) and triethylamine (17 mg, 0.17 mmol) intetrahydrofuran (4 mL), was added 2,4-difluoro-1-isocyanatobenzene (21mg, 0.14 mmol). The resulting mixture was then stirred at roomtemperature for 12 h. The reaction was quenched byaddition of water/ice(20 mL), and extracted with ethyl acetate (10 mL×3). The organic phasewas washed with brine (30 mL×2), dried over anhydrous sodium sulfate andconcentrated under vacuum. The residue was purified by Pre-TLC to affordthe desired product (15.7 mg, 27% yield). LCMS (ES, m/z): 510.5 [M+H]⁺;¹HNMR: (300 MHz, DMSO-d₆, ppm): δ 13.01 (brs, 1H), 9.31 (s, 1H), 8.1 (s,1H), 7.97-7.85 (m, 2H), 7.31 (t, J=6 Hz, 1H), 7.17 (d, J=6 Hz , 1H),7.06 (t, J=6 Hz, 1H), 6.93 (t, J=6 Hz, 1H), 3.25 (s, 1H), 3.00-2.86 (m,3H), 2.67 (d, J=6 Hz, 4H), 1.70-1.61 (m, 2H), 0.91 (s, 12H).

Example 30

Step 1. Synthesis of 30-1

To a solution of1-[3-amino-4-[bis(2-methylpropyl)amino]phenyl]-3,3-difluorocyclobutane-1-carbonitrile(500 mg, 1.49 mmol) and triethylamine (196 mg, 1.94 mmol) indichloromethane (5 mL), was added 2,4-difluoro-1-isocyanatobenzene (254mg, 1.64 mmol). The resulting mixture was then stirred at roomtemperature for 12 h. The reaction was quenched by addition of water/ice(50 mL), extracted with ethyl acetate (30 mL×3), and washed with brine(50 mL×2). The organic layer was dried over anhydrous sodium sulfate andconcentrated under vacuum. The residue was purified by silica gel columnwith ethyl acetate/petroleum ether (1/20) as the eluent to afford thedesired product (700 mg, 96% yield).

Step 2 Synthesis of 30

A solution of1-[2-[bis(2-methylpropyl)amino]-5-(1-cyano-3,3-difluorocyclobutyl)phenyl]-3-(2,4-difluorophenyl)urea(500 g, 1.02 mol), trimethylsilyl azide (1.2 g, 10.42 mmol) andtetrabutylammonium fluoride (2.7 g, 10.33 mmol) was stirred at 85° C.for 12 h. The reaction was then cooled to room temperature, and quenchedby addition of water/ice (100 mL). The mixture was extracted with ethylacetate (100 mL×3), and washed with brine (50 mL×2). The organic layerwas dried over anhydrous sodium sulfate and concentrated under vacuum.The residue was purified by by Prep-HPLC with the following conditions:[Column: X Bbridge Prep C18 OBD,19×150 nm 5 um; mobile phase water(0.05% TFA) and ACN/MEOH (15% up to 60.0% in 8 min); Detector, UV 254nm] to afford the desired product (132.9 mg, 24% yield) as a whitesolid. LCMS (ES, m/z): 534.2 [M+H]⁺. ¹HNMR: (300 MHz, DMSO-d₆, ppm): δ9.33 (s, 1H), 8.06 (s, 1H), 7.96-7.87 (m, 2H), 7.31 (t, J=6 Hz, 1H),7.19 (d, J=8.4 Hz, 1H), 7.08-6.95 (m, 2H), 3.44-3.35 (m, 4H), 2.66 (d,J=6.9 Hz, 4H), 1.68-1.59 (m, 2H), 0.83 (d, J=6 Hz ,12H).

Example 31

Step 1. Synthesis of 31-2

A solution of 4-fluoro-3-nitrophenol (1 g, 6.37 mmol) and potassiumcarbonate (1.76 g, 12.73 mmol) in N,N-dimethylformamide (15 mL) wascooled to 0° C. Methyl 2-bromoacetate (1.17 g, 7.65 mmol) was addeddropwise. The mixture was stirred at room temperature for overnight. Thereaction was then quenched by the addition of water (15 mL), andextracted with ethyl acetate (50 mL×3). The organic layer was washedwith brine (50 mL×3), dried over anhydrous sodium sulfate, andconcentrated under vacuum. The residue was purified by silica gel columnwith ethyl acetate/petroleum ether (1:10-1:5) as the eluent to affordthe desired product (800 mg, 55% yield).

Step 2. Synthesis of 31-3

A solution of methyl 2-(4-fluoro-3-nitrophenoxy)acetate (800 mg, 3.49mmol), bis(2-methylpropyl)amine (676 mg, 5.23 mmol), andN-ethyl-N-isopropylpropan-2-amine (1.35 g, 10.45 mmol) in dimethylsulphoxide (10 mL) was stirred at 60° C. for 4 h. The reaction was thencooled to room temperature and diluted with water (10 mL). The mixturewas extracted with ethyl acetate (50 mL×3). The organic layer was washedwith brine (50 mL×3), dried over anhydrous sodium sulfate, andconcentrated under vacuum. The residue was purified by silica gel columnwith ethyl acetate/petroleum ether (1:20-1:5) as the eluent to affordthe desired product (800 mg, 68% yield).

Step 3. Synthesis of 31-4

To a solution of methyl2-[4-[bis(2-methylpropyl)amino]-3-nitrophenoxy]acetate (800 mg, 2.36mmol) in ethyl acetate (10 mL) and methanol (1 mL), palladium on carbon(500 mg) was added. The mixture was stirred at room temperature for 2 hunder hydrogen balloon. The solid was filtered off and washed withmethanol (10 mL×3). The filtrate was concentrated under vacuum and theresidue was purified by silica gel column with ethyl acetate/petroleumether (1:10˜1:3) as the eluent to afford the desired product (400 mg,55% yield).

Step 4. Synthesis of 31-5

To a solution of methyl2-[3-amino-4-[bis(2-methylpropyl)amino]phenoxy]acetate (300 mg, 0.97mmol) in tetrahydrofuran (5 mL), was added triethylamine (147 mg, 1.45mmol) and then 2,4-difluoro-1-isocyanatobenzene (181 mg, 1.17 mmol). Themixture was stirred at room temperature for 2 h and then concentratedunder vacuum. The residue was purified by silica gel column with ethylacetate/petroleum ether (1:10-1:3) as the eluent to afford the desiredproduct (180 mg, 40% yield).

Step 5. Synthesis of 31

To a solution of methyl2-[4-[bis(2-methylpropyl)amino]-3-[[(2,4-difluorophenyl)carbamoyl]amino]phenoxy]acetate(150 mg, 0.32 mmol) in tetrahydrofuran (5 mL) and methanol (1 mL),sodium hydroxide (0.3 mL, 15% aq.) was added. The reaction was stirredat room temperature for 2 h. The mixture was concentrated under vacuumand the residue was purified by Prep-HPLC with the following conditions:[Column, Waters X-bridge RP18, 19*150 mm, 5 um; mobile phase, ACN/water(0.05% TFA) from 17% to 43% within 7 min, flow rate: 20 mL/min;Detector, 254 nm] to afford the desired product (30.7 mg, 21% yield) asan off-white solid. LCMS (ES, m/z): 450.2 [M+H]⁺; 1HNMR: (300 MHz,DMSO-d₆, ppm): δ 12.90 (s, 1H), 9.33 (s, 1H), 8.23 (s, 1H), 7.91-7.82(m, 1H), 7.59 (d, J=2.7 Hz, 1H), 7.33-7.25 (m, 1H), 7.12 (d, J=8.7 Hz,1H), 7.08-7.02 (m, 1H), 6.51 (dd, J=8.7, 2.7 Hz, 1H), 4.54 (s, 2H), 2.61(d, J=6.9 Hz, 4H), 1.64-1.55 (m, 2H), 0.83 (d, J=6.6 Hz, 12H).

Example 32

Step 1. Synthesis of 32-1

To a solution of 4-fluoro-3-nitrophenol (10 g, 63.65 mmol) and potassiumcarbonate (17 g, 123.00 mmol) in N,N-dimethylformamide (40 mL), wasadded methyl 2-bromo-2-methylpropanoate (23 g, 127.05 mmol). Afterstirring at 60° C. for 2.5 h, the reaction was quenched by addition ofwater (150 mL), and the mixture was extracted with ethyl acetate. Theorganic phase was washed with brine, dried over anhydrous sodiumsulfate, and concentrated under vacuum. The residue was purified bysilica gel column with ethyl acetate/petroleum ether (1/50) as eluent toafford the desired product (11 g, 67% yield).

Step 2. Synthesis of 32-2

A solution of methyl 2-(4-fluoro-3-nitrophenoxy)-2-methylpropanoate (10g, 38.88 mmol), diisopropylethylamine (10 g, 77.38 mmol) andbis(2-methylpropyl)amine (7 g, 54.16 mmol) in dimethylsulfoxide (40 mL)was stirred at 100° C. overnight. After cooled to room temperature, thereaction was quenched with water (100 mL), and extracted with ethylacetate. The organic phase was washed with water, brine, dried overanhydrous sodium sulfate, and concentrated under vacuum to afford thedesired product (11 g, 77% yield).

Step 3. Synthesis of 32-3

A mixture of methyl2-[4-[bis(2-methylpropyl)amino]-3-nitrophenoxy]-2-methylpropanoate (6 g,16.37 mmol) and palladium on carbon (0.9 g) in methanol (20 mL) wasstirred under hydrogen balloon at room temperature for overnight. Themixture was filtered through Celite and the filtrate was concentratedunder vacuum. The residue was purified by silica gel column with ethylacetate/petroleum ether (1/20) as eluent to afford the desired product(3.1 g, 56% yield).

Step 4. Synthesis of 32-4

To a solution of methyl2-[3-amino-4-[bis(2-methylpropyl)amino]phenoxy]-2-methylpropanoate (500mg, 1.49 mmol) in tetrahydrofuran (10 mL), were added triethylamine (451mg, 4.46 mmol) and then 2,4-difluoro-1-isocyanatobenzene (346 mg, 2.23mmol). The resulting mixture was then stirred at room temperature for 3h. The reaction was quenched by addition of water, and extracted withethyl acetate. The organic layer was washed with water and brine, driedover anhydrous sodium sulfate, and concentrated under vacuum. Theresidue was purified by silica gel column with ethyl acetate/petroleumether (1/25) as eluent to afford the desired product (570 mg, 78%yield).

Step 5. Synthesis of 32

A mixture of 32-4 (650 mg, 1.32 mmol), lithium hydroxide (64 mg, 2.67mmol) in tetrahydrofuran (8 ml) and water (4 ml) was stirred at roomtemperature for 20 h. The pH value of the solution was adjusted to 7with aqueous hydrogen chloride (2 N). The mixture was then extractedwith ethyl acetate. The organic phase was washed with brine, dried overanhydrous sodium sulfate, and concentrated under vacuum. The residue waspurified by Prep-HPLC (column: XBridge Shield RP18 OBD Column, 5 um,19×150 mm; mobile phase A: water with 0.05% ammonium bicarbonate, mobilePhase B: acetonitrile; flow rate: 25 mL/min; gradient: 25% B to 85% B in8 min; detector: UV 254 nm). The collected fraction was concentrated toafford the desired product (95.3 mg, 14% yield) as a white solid. LRMS(ES, m/z): 478.3 [M+H]⁺. ¹HNMR (300 MHz, DMSO-D₆, ppm) δ 9.29 (s, 1H),8.11 (s, 1H), 7.92-7.84 (m, 1H), 7.44 (d, J=3 Hz, 1H), 7.34-7.26 (m,1H), 7.08-7.02 (m, 2H), 6.48 (dd, J=8.4 Hz, J=2.4 Hz, 1H), 2.58 (d,J=6.9 Hz, 4H), 1.63-1.58 (m, 2H), 1.42 (s, 6H), 0.83 (d, J=6.6 Hz, 12H).

Example 33

Step 1. Synthesis of 33-1

To a solution of pyrimidin-5-amine (565 mg, 5.94 mmol) anddiisopropylethylamine (1.046 g, 8.09 mmol) in dichloromethane (12 mL),was added a solution of ditrichloromethyl carbonate (601 mg, 2.03 mmol)in dichloromethane (6 mL). The resulting mixture was stirred at roomtemperature for 15 min, and 32-3 (500 mg, 1.49 mmol) and triethylamine(902 mg, 8.91 mmol, 6.00 equiv) were added sequencially. The reactionmixture was stirred at room temperature for 5 h and then the reactionwas quenched by addition of methanol and then water. The reaction wasextracted with dichloromethane, washed with water and brine, and driedover anhydrous sodium sulfate. After concentration, the residue waspurified by silica gel column with ethyl acetate/petroleum ether (1/5)as the eluent to afford the desired product (570 mg, 84% yield).

Step 2. Synthesis of 33

A mixture of 33-1 (500 mg, 1.09 mmol), lithium hydroxide (53 mg, 2.21mmol) in tetrahydrofuran (6 mL) and water (4 mL) was stirred at roomtemperature for overnight. The pH value of the solution was adjusted to7 with aqueous hydrogen chloride (2 N). The product was extracted withethyl acetate, washed with brine, dried over anhydrous sodium sulfate,and concentrated under vacuum. The residue was purified by Prep-HPLC(Column: XBridge Shield RP18 OBD Column, 5 um, 19×150 mm; Mobile PhaseA: Water with 0.05% NH₄HCO₃, Mobile Phase B: ACN; Flow rate: 25 mL/min;Gradient: 25% B to 85% B in 8 min; detector: UV 254 nm). The collectedfraction was concentrated to afford the desired product (122.9 mg, 25%yield) as a white solid. LRMS (ES, m/z): 444.4 [M+H]⁺. ¹HNMR (300 MHz,DMSO-D₆, ppm) δ 9.92 (s, 1H), 8.91 (s, 2H), 8.82 (s, 1H), 8.20 (s, 1H),7.58 (d, J=2.4 Hz, 1H), 7.12 (d, J=8.4 Hz, 1H), 6.49 (d, J=8.4 Hz, 1H),2.62 (d, J=6.6 Hz, 4H), 1.62 (m, 2H), 1.47 (s, 6H), 0.85 (d, J=6.6 Hz,12H).

Example 34

Step 1. Synthesis of 34-1

To a solution of 3-methyl-1,2-oxazol-5-amine (583 mg, 5.94 mmol) anddiisopropylethylamine (1.04 g, 8.08 mmol) in dichloromethane (12 mL),was added dropwise a solution of ditrichloromethyl carbonate (601 mg,2.03 mmol) in dichloromethane (6 mL). The resulting mixture was stirredat room temperature for 20 min. A solution of 32-3 (500 mg, 1.49 mmol)in dichloromethane (2 mL) and triethylamine (902 mg, 8.91 mmol) wasadded and the reaction mixture was stirred at room temperature foranother 5 h. Water and dichloromethane were added. The organic phase wasseparated, washed with brine, dried over anhydrous sodium sulfate, andconcentrated under vacuum. The residue was purified by silica gel columnwith ethyl acetate/petroleum ether (1/20) as the eluent to afford thedesired product (580 mg, 85% yield).

Step 2. Synthesis of 34

A mixture of 34-1 (500 mg, 1.09 mmol), lithium hydroxide (52 mg, 2.17mmol) in tetrahydrofuran (6 mL) and water (4 mL) was stirred at roomtemperature for overnight. The pH value of the solution was adjusted to7 with aqueous hydrogen chloride (2 N). The product was extracted withethyl acetate, washed with brine, dried over anhydrous sodium sulfate,and concentrated under vacuum. The residue was purified by Prep-HPLC(column: XBridge Shield RP18 OBD Column, 5 um, 19×150 mm; mobile phaseA: water with 0.05% ammonium bicarbonate, mobile Phase B: acetonitrile;flow rate: 25 mL/min; gradient: 25% B to 85% B in 8 min; detector: UV254 nm). The collected fraction was concentrated to afford the desiredproduct (58.8 mg, 12% yield) as white solid. LRMS (ES, m/z): 447.3[M+H]⁺. ¹HNMR: (300 MHz, DMSO-D₆, ppm) δ 11.23 (s, br, 1H), 8.25 (s,1H), 7.53 (d, J=2.4 Hz, 1H), 7.10 (d, J=8.7 Hz, 1H), 6.50 (dd, J=8.7 Hz,J=2.4 Hz, 1H), 5.95 (s, 1H), 2.58 (d, J=6.6 Hz, 4H), 2.17 (s, 3H),1.62-1.51 (m, 2H), 1.46 (s, 6H), 0.84 (d, J=6.3 Hz, 12H).

Example 35

Step 1. Synthesis of 35-1

A solution of methyl 2-(4-fluoro-3-nitrophenoxy)-2-methylpropanoate (500mg, 1.95 mmol), N-isobutylcyclohexanamine (450 mg, 2.93 mmol) andN,N-diisopropylethylamine (750 mg, 5.85 mmol) in dimethyl sufoxide (10mL) was stirred at 110° C. for overnight. The reaction was cooled toroom temperature and diluted with ethyl acetate (100 mL). The mixturewas washed with water (60 mL) and brine (60 mL). The organic phase wasdried over anhydrous sodium sulfate and concentrated under vacuum. Theresidue was purified by silica gel column with ethyl acetate/petroleumether (1/8) as the eluent to afford the desired product (250 mg, 33%yield).

Followed similar steps 3-5 in example 32 to synthesize 35

Example 35: LCMS (ES, m/z): 504.4 [M+H]⁺; ¹HNMR (300 MHz, DMSO-d₆, ppm):δ 9.38 (s, 1H), 8.27 (s, 1H), 7.91-7.83 (m, 1H), 7.55 (s, 1H), 7.34-7.25(m, 1H), 7.08-6.98 (m, 2H), 6.44 (d, J=9.0 Hz, 1H), 2.83-2.62 (m, 3H),1.96-1.81 (m, 2H), 1.78-1.61 (m, 2H), 1.58-1.26 (m, 8H), 1.23-1.11 (m,5H), 0.82 (d, J=6.6 Hz, 6H).

Example 36

Step 1. Synthesis of 36-1

Into a 50-mL 3-bottom flask purged and maintained under an inertatmosphere of nitrogen, was placed sulfurochloridic acid (19.6 g, 168.21mmol). This was followed by addition of 1-fluoro-2-nitrobenzene (10 g,70.87 mmol) dropwise with stirring at 65° C. in 5 min. The resultingsolution was stirred at 90° C. for overnight. The reaction was cooled toroom temperature, and then poured into 50 mL of water/ice. The mixturewas extracted with 3×50 mL of dichloromethane. The organic layer waswashed with 100 mL of saturated sodium bicarbonate and then 2×100 mL ofbrine, dried over anhydrous sodium sulfate, and concentrated undervacuum to afford the desired product (9 g, 53% yield).

Step 2. Synthesis of 36-2

Into a 250-mL 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed a solution of4-fluoro-3-nitrobenzene-1-sulfonyl chloride (9 g, 37.56 mmol) in toluene(90 mL). This was followed by addition of PPh₃ (29.5 g, 112.47 mmol) inseveral batches in 60 min (exothermic). The resulting solution wasstirred for 1 h. To this, water (50 mL) was carefully added maintainingthe reaction temperature less than 45° C. The resulting solution wasstirred for 1 h at room temperature. The reaction mixture was extractedwith 3×100 mL of dichloromethane. The combined organic layers werewashed with 3×200 mL of brine, dried over anhydrous sodium sulfate, andconcentrated under vacuum. The residue was applied onto a silica gelcolumn with ethyl acetate/petroleum ether (1:10-1:3) to afford thedesired product (4 g, 61% yield).

Step 3. Synthesis of 36-3

Into a 100-mL 3-necked round-bottom flask purged and maintained under aninert atmosphere of nitrogen, was placed a solution of4-fluoro-3-nitrobenzene-1-thiol (4 g, 23.10 mmol) and methyl2-bromoacetate (4.24 g, 27.72 mmol) in N,N-dimethylformamide (50 mL).This was followed by the addition of DIEA (5.97 g, 46.19 mmol) dropwisewith stirring at 0° C. in 10 min. The resulting solution was stirred at50° C. for overnight. The reaction mixture was cooled to roomtemperature. The resulting solution was diluted with 50 mL of H₂O. Thereaction was extracted with 3×50 mL of ethyl acetate. The combinedorganic layers were washed with 3×50 mL of brine, dried over anhydroussodium sulfate, and concentrated under vacuum. The residue was appliedonto a silica gel column with ethyl acetate/petroleum ether (1:10-1:3)to afford the desired product (4 g, 71% yield).

Step 4. Synthesis of 36-4

Into a 100-mL 3-necked round-bottom flask purged and maintained under aninert atmosphere of nitrogen, was placed a solution of methyl2-[(4-fluoro-3-nitrophenyl)sulfanyl]acetate (4 g, 16.31 mmol),bis(2-methylpropyl)amine (3.16 g, 24.45 mmol, 1.5 equiv), and DIEA (4.2g, 32.50 mmol, 2.0 equiv) in DMSO (40 mL). The reaction was stirred at80° C. for overnight. The mixture was cooled to room temperature. Theresulting solution was diluted with 40 mL of H₂O, and extracted with3×50 mL of ethyl acetate. The combined organic layer was washed with3×50 mL of brine, dried over anhydrous sodium sulfate, and concentratedunder vacuum. The residue was applied onto a silica gel column withethyl acetate/petroleum ether (1:10-1:3) to afford the desired product(3.1 g, 54% yield).

Step 5. Synthesis of 36-5

Into a 100-mL round-bottom flask, was placed a solution of methyl2-([4-[bis(2-methylpropyl)amino]-3-nitrophenyl]sulfanyl)acetate (3 g,8.46 mmol) and palladium on carbon (100 mg) in ethyl acetate (30 mL) andMeOH (5 mL). The flask was evacuated and flushed three times withnitrogen, followed by flushing with hydrogen. The mixture was stirred 3h at room temperature under an atmosphere of hydrogen (balloon).Thesolid was filtered off The filtrate was concentrated under vacuum toafford the desired product (2 g, 73% yield).

Step 6. Synthesis of 36-6

Into a 100-mL 3-necked round-bottom flask, was placed a solution ofmethyl 2-([3-amino-4-[bis(2-methylpropyl)amino]phenyl]sulfanyl)acetate(2 g, 6.16 mmol), 2,4-difluoro-1-isocyanatobenzene (1.15 g, 7.41 mmol),and triethylamine (1.25 g, 12.35 mmol) in tetrahydrofuran (50 mL). Thereaction was stirred at room temperature for overnight. The resultingmixture was concentrated under vacuum. The residue was applied onto asilica gel column with ethyl acetate/petroleum ether (1:10-1:1) toafford the desired product (1.5 g, 51% yield).

Step 7. Synthesis of 36

To a solution of methyl2-([4-[bis(2-methylpropyl)amino]-3-[[(2,4-difluorophenyl)carbamoyl]amino]phenyl]sulfanyl)acetate(250 mg, 0.52 mmol) in ethanol (3 mL) and H₂O (0.5 mL), was added sodiumhydroxide (15% aq) (0.5 mL). The resulting solution was stirred at roomtemperature for 3 h. The pH value of the solution was adjusted to 6 withhydrogen chloride (1 N). The resulting mixture was concentrated undervacuum. The crude product was purified by Prep-HPLC with the followingconditions: Column, Waters X-bridge RP18, 19*150 mm, 5 um; mobile phase,ACN/water (0.05% NH₃H₂O) from 15% to 40% within 6.5 min, flow rate: 20mL/min; Detector, 254 nm. This resulted in the desired product (60 mg,25% yield) as a white solid. LCMS (ES, m/z): 466 [M+H]⁺. HNMR (300 MHz,DMSO-d₆, ppm): δ 9.33 (s, 1H), 8.10 (s, 1H), 7.97-7.88 (m, 2H), 7.30 (t,J=6.6 Hz, 1H), 7.28 (d, J=6.0 Hz, 1H), 7.17-7.02 (m, 1H), 6.94 (dd,J=8.4, 2.4 Hz, 1H), 3.38 (s, 2H), 2.67 (d, J=6.9 Hz, 4H), 1.69-1.60 (m,2H), 0.83 (d, J=6.6 Hz, 12H).

Example 37

Step 1. Synthesis of 37-1

To a solution of 4-bromo-1-fluoro-2-nitrobenzene (5 g, 22.73 mmol) indimethyl sulfoxide (50 mL) were added bis(2-methylpropyl)amine (3.53 g,27.31 mmol) and then N,N-diisopropylethylamine (3.53 g, 27.36 mmol). Thereaction was then stirred at 100° C. for 12 h. After cooling to roomtemperature, the mixture was diluted with water (200 mL), and extractedwith ethyl acetate (200 mL×3). The organic phase was washed with brine(200 mL) and concentrated under vacuum to afford the desired product (7g, 94% yield).

Step 2. Synthesis of 37-2

A solution of 4-bromo-N,N-bis(2-methylpropyl)-2-nitroaniline (7 g, 21.26mmol), phenylmethanethiol (3.125 g, 25.16 mmol), Pd₂(dba)₃CHCl₃ (2.2 g,2.13 mmol), XantPhos (1.23 g, 2.12 mmol), and triethylamine (4.31 g,42.67 mmol) in dioxane (100 mL) was stirred at 100° C. for 2 h. Aftercooling to room temperature, the mixture was concentrated under vacuum.The residue was purified by silica gel column with ethylacetate/petroleum ether (1/15-1/10) as the eluent to afford the desiredproduct (4 g, 51% yield).

Step 3. Synthesis of 37-3

To a solution of4-(benzylsulfanyl)-N,N-bis(2-methylpropyl)-2-nitroaniline (1 g, 2.68mmol) in ethanol (20 mL) and water (2 mL), was added iron (750 mg, 13.43mmol) and then ammonium chloride (710 mg, 13.40 mmol). The reaction wasthen stirred at 80° C. for 1 h. After cooling to room temperature, themixture was diluted with water (50 mL), and extracted with ethyl acetate(50 mL×3). The organic phase was concentrated under vacuum and theresidue was purified by silica gel column with ethyl acetate/petroleumether (1/10-1/3) as the eluent to afford the desired product (340 mg,37% yield).

Step 4. Synthesis of 37-4

To a solution of4-(benzylsulfanyl)-1-N,1-N-bis(2-methylpropyl)benzene-1,2-diamine (200mg, 0.58 mmol) and triethylamine (71 mg, 0.70 mmol) in tetrahydrofuran(10 mL) was added 2,4-difluoro-1-isocyanatobenzene (109 mg, 0.70 mmol).The reaction was then stirred at room temperature for 30 min. Thereaction was quenched by addition of water (10 mL), and the mixture wasextracted with ethyl acetate (15 mL×3). The combined organic layer waswashed with 3×50 mL of brine, dried over anhydrous sodium sulfate, andconcentrated under vacuum to afford the desired product (150 mg, 52%yield).

Step 5. Synthesis of 37-5

To a solution of3-[5-(benzylsulfanyl)-2-[bis(2-methylpropyl)amino]phenyl]-1-(2,4-difluorophenyl)urea(150 mg, 0.30 mmol) in Toluene (5 mL) was added aluminium chloride (398mg, 2.98 mmol) portionwise. The resulting mixture was then stirred atroom temperature for 2 h. The reaction was diluted with water (10 mL),and extracted with ethyl acetate (15 mL×3). The combined organic layerwas washed with 3×50 mL of brine, dried over anhydrous sodium sulfate,and concentrated under vacuum to afford the desired product (70 mg, 57%yield).

Step 6. Synthesis of 37-6

To a solution of3-[2-[bis(2-methylpropyl)amino]-5-sulfanylphenyl]-1-(2,4-difluorophenyl)urea(70 mg, 0.17 mmol) and N,N-diisopropylethylamine (33.5 mg, 0.26 mmol) indimethyl sulfoxide (1 mL), was added ethyl 2-bromo-2-methylpropanoate(36.7 mg, 0.19 mmol). The reaction was stirred at room temperature for 1h. The mixture was diluted with water (5 mL), and extracted with ethylacetate (5 mL×3). The organic phase was washed with brine (5 mL), driedover anhydrous sodium sulfate, and concentrated under vacuum. Theresidue was purified by silica gel column with ethyl acetate/petroleumether (1/5-1/3) as the eluent to afford the desired product (60 mg, 67%yield).

Step 7. Synthesis of 37

To a solution of ethyl2-([4-[bis(2-methylpropyl)amino]-3-[[(2,4-difluorophenyl)carbamoyl]amino]phenyl]sulfanyl)-2-methylpropanoate(60 mg, 0.12 mmol) in tetrahydrofuran (1 mL) and water (0.2 mL), wasadded lithium hydroxide monohydrate (6.9 mg, 0.29 mmol). The reactionwas stirred at 60° C. for 12 h. After cooling to room temperature, themixture was concentrated under vacuum and the residue was purified byFlash-Prep-HPLC [Column: Waters X-bridge C18, 5 um, 19×150 mm; Mobilephase A: water (0.05% NH₄HCO₃), Mobile phase B: CAN; Gradient: 50% ACNto 90% CAN in 10 min; Detector: UV 254 nm] to afford the desired product(12 mg, 21% yield) as a white solid. LCMS: (ES, m/z): 494.2 [M+H]⁺.¹HNMR: (300 MHz, CD₃OD): δ 8.03 (s, 1H), 7.84-7.76 (m, 1H), 7.20-7.12(m, 2H), 7.06-6.91 (m, 2H), 2.74 (d, J=14.1 Hz, 4H), 1.78-1.69 (m, 2H),1.46 (s, 6H), 0.87 (d, J=6.6 Hz, 12H).

Example 38

Step 1. Synthesis of 38-1

To a solution of 4-(benzylthio)-N1,N1-diisobutylbenzene-1,2-diamine (600mg, 1.75 mmol) in tetrahydrofuran (10 mL), was added5-isocyanatopyrimidine (862 mg, 7.12 mmol) and then triethylamine (930mg, 9.19 mmol). The reaction was stirred at room temperature for 2 h.The mixture was diluted with water (50 mL), and extracted with ethylacetate (50 mL×3). The organic phase was washed with brine (50 mL×2),dried over anhydrous sodium sulfate, and concentrated under vacuum. Theresidue was purified by silica gel column with ethyl acetate/petroleumether (2/3) as the eluent to afford the desired product (600 mg, 74%yield).

Followed similar steps 5-7 in example 37 to synthesize 38

Example 38: LCMS (ES, m/z): 460.2 [M+H]⁺. ¹H NMR (300 MHz, CD₃OD): δ8.97 (s, 2H), 8.79 (s, 1H), 8.15 (s, 1H), 7.20 (s, 2H), 2.75(d, J=6.9Hz, 4H), 1.79-1.70 (m, 2H), 1.45 (s, 6H), 0.91 (d, J=6.6 Hz, 12H).

Example 39

Step 1. Synthesis of 39-1

To a solution of 4-(benzylthio)-N1,N1-diisobutylbenzene-1,2-diamine (175mg, 0.51 mmol) in tetrahydrofuran (10 mL), was added5-isocyanato-3-methylisoxazole (253 mg, 2.04 mmol) and thentriethylamine (310 mg, 3.07 mmol). The reaction was then stirred at roomtemperature for overnight, at 45° C. for 12h, and then at 75° C. for 36h. The mixture was cooled to room temperature, and then quenched byaddition of water/ice (50 mL). The mixture was extracted with ethylacetate (20 mL×3), and washed with brine (20 mL×2). The organic phasewas dried over anhydrous sodium sulfate and concentrated under vacuum toafford the desired product (100 mg, 42% yield).

Followed similar steps 5-7 in example 37 to synthesize 39

Example 39: LCMS (ES, m/z): 463.6 [M+H]⁺. ¹HNMR: (300 MHz, CH₃OD, ppm):δ 8.15 (s, 1H), 7.20 (s, 2H), 6.06 (s, 1H), 2.73 (d, J=6.9 Hz, 4H), 2.24(s, 3H), 1.77-1.66 (m, 2H), 1.45 (s, 6H), 0.89 (d, J=6.6 Hz, 12H).

Example 40

Step 1. Synthesis of 40-1

Into a 50 mL sealed tube, were added cyclohexanamine (2 g, 20.17 mmol),2,2-dimethyloxirane (1.45 g, 20.11 mmol), and ethanol (10 mL). Theresulting solution was stirred at 100° C. for 2 days. After cooling toroom temperature, petroleum ether (20 mL) was added and the solid wasfiltered off. The filtrate was concentrated under vacuum and the crudeproduct was purified by silica gel column with methanol anddichloromethane (1:10) as eluent to afford the desired product (2.4 g,69% yield).

Step 2. Synthesis of 40-2

To a solution of 4-bromo-1-fluoro-2-nitrobenzene (1.45 g, 6.57 mmol) anddiisopropylethylamine (1.70 g, 13.15 mmol) in dimethylsulfoxide (10 mL),was added 41-1 (1.35 g, 7.88 mmol). The reaction mixture was stirred at120° C. for 1 day. The reaction was quenched by addition of water (100mL) and the mixture was extracted with ethyl acetate (50 mL×3). Thecombined organic layer was dried over anhydrous sodium sulfate andconcentrated under vacuum. The residue was purified by silica gel columnwith ethyl acetate/petroleum ether (1/10) as eluent to afford thedesired product (1.42 g, 58% yield).

Followed similar steps 2-7 in example 37 to synthesize 40.

Example 40: LRMS (ES, m/z) 536.4[M+H]⁺. ¹HNMR (300 MHz, MeOD, ppm) 8.14(s, 1H), 8.14-7.93 (m, 1H), 7.27 (d, J=8.4 Hz, 1H), 7.25-7.14 (m, 1H),7.07-6.92 (m, 2H), 4.62 (br, 1H), 3.14 (br, 2H), 2.61-2.60 (m, 1H), 1.93(d, J=10.8 Hz, 2H), 1.74 (d, J=10.4 Hz, 2H), 1.57 (d, J=11.1 Hz, 1H),1.44 (s, 6H), 1.36-1.03 (m, 5H), 1.00 (s, 6H).

Example 41

Step 1. Synthesis of 41-1

A solution of N-isobutylcyclohexanamine (1.0 g, 6.45 mmol),4-bromo-1-fluoro-2-nitrobenzene (1.42 g, 6.45 mmol), andN,N-diisopropylethylamine (1.66 g, 12.9 mmol) in dimethyl sufoxide (20mL) was stirred at 110° C. for overnight. The reaction was cooled toroom temperature, and diluted with ethyl acetate (100 mL). The organicphase was washed with water (60 mL) and brine (60 mL), dried overanhydrous sodium sulfate, and concentrated under vacuum. The residue waspurified by silica gel column with ethyl acetate/petroleum ether (1/10)as the eluent to afford the desired product (1.34 g, 59% yield).

Followed similar steps 2-7 in example 37 to synthesize 41

Example 41: LCMS (ES, m/z): 520.4 [M+H]⁺; ¹HNMR (300 MHz, DMSO-d₆, ppm):δ 12.72 (brs, 1H), 9.40 (s, 1H), 8.09 (s, 1H), 8.02 (s, 1H), 8.01-7.88(m, 1H), 7.36-7.28 (m, 1H), 7.17-7.14 (m, 1H), 7.06-7.04 (m, 2H), 2.79(d, J=6.0 Hz, 2H), 2.62-2.55 (m, 1H), 1.86-1.83 (m, 2H), 1.78-1.66 (m,2H), 1.58-1.48 (m, 1H), 1.42-1.23 (m, 8 H), 1.21-0.98 (m, 4H), 0.82 (d,J=6.6 Hz, 6H).

Example 42

Step 1. Synthesis of 42-1

To a solution of 4-bromo-1-fluoro-2-nitrobenzene (6.1 g, 27.73 mmol) inDMSO (2 mL), was added diisopropylethylamine (7.2 g, 55.81 mmol) andthen N-ethyloxan-4-amine (2.4 g, 18.58 mmol). After stirring at 140° C.for overnight, the reaction mixture was cooled to room temperature andwater (60 mL) was added. The reaction mixture was extracted with ethylacetate (60 mL×3). The combined organic layer was washed with brine (60mL×2), dried over anhydrous sodium sulfate, and concentrated undervacuum. The residue was purified by column chromatography on silica gelwith ethyl acetate/petroleum ether (1/40) to affordN-(4-bromo-2-nitrophenyl)-N-ethyloxan-4-amine (5.5 g, 60% yield).

Followed similar steps 2-7 in example 37 to synthesize 42.

Example 42: LC-MS (ES, m/z): [M+H]⁺ 494.4. ¹HNMR (300 MHz, DMSO-d₆,ppm): δ 9.43 (s, 1H), 8.78 (s, 1H), 8.27 (d, J=2.1 Hz, 1H), 8.06-7.98(m, 1H), 7.34-7.26 (m, 1H), 7.20 (d, J=8.1 Hz, 1H), 7.07-7.00 (m, 2H),3.82 (d, J=1.2 Hz, 2H), 3.27-3.18 (m, 2H), 3.03-2.95 (m, 3H), 1.69 (d,J=6.6 Hz, 2H), 1.45-1.22 (m, 8H), 0.79 (t, J=6.9 Hz, 3H).

Example 43

Step 1. Synthesis of 43-1

To a solution of oxan-4-one (7.5 g, 75 mmol) in tetrahydrofuran (60 mL)at room temperature, was added 2-methylpropan-1-amine (4.96 g, 68 mmol)and then acetic acid (1.5 mL). The resulting solution was stirred for 1h at room temperature. To this was added NaBH(OAc)₃ (28.83 g). Afterstirring at room temperature for overnight, the reaction was quenched byaddition of water (50 mL) and the mixture was extracted with ethylacetate (60 mL×3). The combined organic layer was washed with brine(60×3), dried over anhydrous sodium sulfate, and concentrated undervacuum to afford N-(2-methylpropyl)oxan-4-amine (6.2 g, crude).

Followed similar steps 2-7 in example 37 to synthesize 43.

Example 43: LC-MS (ES, m/z): 522.4 [M+H]⁺. ¹HNMR (300 MHz, CDCl₃-d₆,ppm) δ 8.53 (s, 1H), 8.03 (s, 1H), 7.64-7.47 (m, 1H), 7.13 -7.05 (m,1H), 6.91 (t, 2H), 3.91 (d, J=11.1 Hz, 2H), 3.25-3.17 (m, 2H), 2.72-2.63(m, 2H), 1.70-1.20 (m, 12H), 0.70 (d, J=6.3 Hz, 6H).

Examnle 44

Step 1. Synthesis of 44-1

To a solution of 2-methylpropan-1-amine (5.76 g, 78.76 mmol) and1-methylpiperidin-4-one (9.80 g, 86.60 mmol) in dichloromethane (130mL), was added sodium cyanoborohydride (50.1 g, 236.39 mmol)portionwise. The reaction was then stirred at room temperature for 16 h.The solid was filtered off and the mixture was diluted with water (500mL). The pH value of the mixture was adjusted to 9 with sodiumbicarbonate. The mixture was extracted with dichloromethane (500 mL×4).The organic phase was washed with brine (1000 mL), dried over anhydroussodium sulfate, and concentrated under vacuum to afford the desiredproduct (6 g, 45% yield).

Step 2. Synthesis of 44-2

A solution of 1-methyl-N-(2-methylpropyl)piperidin-4-amine (1.98 g,11.64 mmol), 4-bromo-1-fluoro-2-nitrobenzene (1.7 g, 7.73 mmol), andN,N-diisopropylethylamine (3.01 g, 23.30 mmol) in dimethyl sulfoxide (20mL) was stirred at 100° C. for 17 h. After cooling to room temperature,the mixture was diluted with water (200 mL), and extracted with ethylacetate (200 mL×3). The organic phase was washed with brine (500 mL×2),dried over anhydrous sodium sulfate, and concentrated under vacuum. Theresidue was purified by Flash-Prep-HPLC with the following conditions:[Column: silica gel; Mobile phase A: petroleum ether, Mobile phase B:ethyl acetate; Gradient: 0% ethyl acetate to 100% ethyl acetate within25 min; Detector: UV 254 nm] to afford the desired product (1.2 g, 42%yield).

Followed similar steps 2-7 in example 37 to synthesize 44.

Example 44: LCMS (ES, m/z): 535.4 [M+H]⁺; ¹H NMR (300 MHz, DMSO-d₆,ppm): δ 9.45 (s, 1H), 8.29 (s, 1H), 8.12 (d, J=2.1 Hz, 1H), 7.98-7.90(m, 1H), 7.35-7.28 (m, 1H), 7.20 (d, J=8.1 Hz, 1H), 7.09-7.02 (m, 2H),2.80-2.72 (m, 4H), 2.66-2.58 (m, 1H), 2.11 (s, 3H), 1.85-1.73 (m, 4H),1.57-1.46 (m, 2H), 1.36-1.29 (m, 7H), 0.82 (d, J=6.6 Hz, 6H).

Example 45

Step 1. Synthesis of 45-1

To a solution of cyclohexanone (7.8 g, 79.48 mmol) and2-methoxyethan-1-amine (5 g, 66.57 mmol) in dichloromethane (75 mL), wasadded acetic acid (0.1 mL). The reaction was stirred at 25° C. for 0.5h. Sodium cyanoborohydride (16.7 g, 265.75 mmol) was added and themixture was stirred at 25° C. for another 5 h. The reaction was quenchedby addition of saturated ammonium chloride solution (50 mL). Theresulting mixture was extracted with dichloromethane (50 mL×2), andwashed with brine (50 mL×2). The organic phase was dried over anhydroussodium sulfate and concentrated under vacuum. The residue was purifiedby silica gel column with ethyl acetate/petroleum ether (1/4-100/1) asthe eluent to afford the desired product (6 g, 57% yield).

Step 2. Synthesis of 45-2

To a solution of N-(2-methoxyethyl)cyclohexanamine (5 g, 31.80 mmol) and4-bromo-1-fluoro-2-nitrobenzene (8.4 g, 38.18 mmol) in dimethylsulfoxide (30 mL), was added N,N-diisopropylethylamine (6.2 g, 47.97mmol). The reaction was then stirred at 100° C. for 16 h. The reactionwas cooled to room temperature, diluted with water (200 mL), andextracted with ethyl acetate (200 mL×2). The organic phase was washedwith water (100 mL×2) and brine (100 mL×2), dried over anhydrous sodiumsulfate, and concentrated under vacuum. The residue was purified byFlash-Prep-HPLC with the following conditions: [Column: C18 silica gel;Mobile phase A: water (0.05% TFA), Mobile phase B: ACN, Gradient: 55%CAN to 100% ACN; Detector: UV 254 nm] to afford the desired product (8g, 70% yield).

Followed similar steps 2-7 in example 37 to synthesize 45

Example 45: LCMS (ES, m/z): 522.2 [M+H]⁺. ¹HNMR: (300 MHz, DMSO-d₆,ppm): δ 9.40 (s, 1H), 8.62 (s, 1H), 8.19 (d, J=1.8 Hz, 1H), 8.01-7.93(m, 1H), 7.35-7.19 (m, 2H), 7.08-7.01 (m, 2H), 3.25-3.14 (m, 4H), 3.12(s, 3H), 2.62-2.80 (m, 1H), 1.80-1.98 (m, 2H), 1.79-1.60 (m, 2H),1.59-1.43 (m, 1H), 1.32 (s, 6H), 1.20-0.90 (m, 5H).

Example 46

Step 1. Synthesis of 46-1

A solution of N-(2-methylpropyl)thian-4-amine (3.1 g, 17.89 mmol),4-bromo-1-fluoro-2-nitrobenzene (3.94 g, 17.91 mmol), andN,N-diisopropylethylamine (4.62 g, 35.75 mmol) in dimethyl sulfoxide (30mL) with stirring at 110° C. for overnight. After cooled down to theroom temperature, the reaction was diluted with ethyl acetate (200 mL).The organic phase was washed with water (80 mL) and brine (80 mL), driedover anhydrous sodium sulfate, and concentrated under vacuum. Theresidue was purified by silica gel column with ethyl acetate/petroleumether (1/10) as the eluent to afford the desired product (1.5 g, 22%yield).

Step 2. Synthesis of 46-2

To a solution ofN-(4-bromo-2-nitrophenyl)-N-(2-methylpropyl)thian-4-amine (1.5 g, 4.02mmol) in dichloromethane (20 mL) was added 3-Chloroperbenzoic acid (2.1g, 12.17 mmol). The reaction was stirred at room temperature for 2 h,and the mixture was then diluted with dichloromethane (50 mL). Thereaction was washed with saturated sodium bisulfite solution (30 mL),water (30 mL), and brine (30 mL). The organic phase was dried overanhydrous sodium sulfate and concentrated under vacuum. The residue waspurified by silica gel column with ethyl acetate/petroleum ether (1/5)as the eluent to afford the desired product (0.6 g, 37% yield).

Step 3. Synthesis of 46-3

A solution of 46-2 (200 mg, 0.49 mmol), phenylmethanethiol (68 mg, 0.55mmol), Pd₂(dba)₃.CHCl₃ (26 mg, 0.03 mmol), XantPhos (30 mg, 0.05 mmol),and triethylamine (76 mg) in 1,4-dioxane (3 mL) was stirred at 100° C.for 1 h. The mixture was then diluted with ethyl acetate (30 mL), andthe solid was filtered off. The filtrate was dried over anhydrous sodiumsulfate and concentrated under vacuum. The residue was purified bysilica gel column with ethyl acetate/petroleum ether (1/5) as the eluentto afford the desired product (150 mg, 68% yield).

Step 4. Synthesis of 46-4

To a solution of 46-3 (150 mg, 0.33 mmol) in acetic acid (5 mL) wasadded iron (187 mg, 3.35 mmol), and the reaction was then stirred atroom temperature for 0.5 h. The mixture was diluted with ethyl acetate(50 mL). The solid was filtered off, and the filtrate was washed withsaturated sodium carbonate solution (30 mL) and brine (30 mL). Theorganic phase was dried over anhydrous sodium sulfate and concentratedunder vacuum. The residue was purified by silica gel column with ethylacetate/petroleum ether (1/5) as the eluent to afford the desiredproduct (130 mg, 93% yield).

Step 5. Synthesis of 46-5

A solution of 46-4 (130 mg, 0.31 mmol), 2,4-difluoro-1-isocyanatobenzene(73 mg, 0.47 mmol) and triethylamine (95 mg, 0.94 mmol) intetrahydrofuran (3 mL) was stirred at room temperature for 30 min. Themixture was diluted with ethyl acetate (30 mL), and washed with water(20 mL) and brine (20 mL). The organic phase was dried over anhydroussodium sulfate and concentrated under vacuum. The residue was purifiedby silica gel column with ethyl acetate/petroleum ether (1/2) as theeluent to afford the desired product (120 mg, 67% yield).

Step 6. Synthesis of 46-6

To a solution of 46-5 (120 mg, 0.21 mmo) in toluene (5 mL) was addedAlCl₃ (240 mg, 1.80 mmol), and the reaction was stirred at roomtemperature for 30 min. The mixture was diluted with water (10 mL) andextracted with ethyl acetate (10 mL×2). The organic phase was dried overanhydrous sodium sulfate and concentrated under vacuum to afford thedesired product (80 mg, 79% yield).

Step 7. Synthesis of 46-7

A solution of ethyl 2-bromo-2-methylpropanoate (51 mg, 0.26 mmol), 46-6(80 mg, 0.17 mmol), and N,N-diisopropylethylamine (44 mg, 0.34 mmol) indimethyl sulfoxide (3 mL) was stirred at room temperature overnight. Thereaction was diluted with ethyl acetate (20 mL), and washed with water(10 mL) and brine (10 mL). The organic phase was dried over anhydroussodium sulfate and concentrated under vacuum. The residue was purifiedby silica gel column with ethyl acetate/petroleum ether (1/5) as theeluent to afford the desired product (70 mg, 71% yield).

Step 8. Synthesis of 46

To a solution of 46-7 (70 mg, 0.12 mmol) in ethanol (1.5 mL) and water(0.5 mL), was added LiOH (160 mg, 6.68 mmol). The resulting mixture wasstirred at 75° C. for 1 h. The reaction was then cooled to roomtemperature and diluted with water (20 mL). The mixture was extractedwith ethyl acetate (30 mL). The organic phase was dried over anhydroussodium sulfate and concentrated under vacuum. The residue was purifiedby Prep-HPLC with the following conditions: [Column: X Bridge ShieldRP18 OBD, 5 um, 19×150 mm; Mobile phase A: Waters (10 mmol/L NH₄HCO₃),Mobile Phase B: CAN; Gradient: 15% ACN to 40% in 8 min; Detector: UV 254nm] to afford the desired product (27.6 mg, 41% yield). LCMS: (ES, m/z):570.2 [M+H]⁺; ¹H NMR (300 MHz, DMSO-d₆): ppm δ 9.48 (s, 1H), 8.18 (s,2H), 8.00-7.92 (m, 1H), 7.36-7.28 (m, 1H), 7.21-7.18 (m, 1H), 7.09-7.03(m, 2H), 3.24-3.15 (m, 2H), 3.10-2.93 (m, 3H), 2.90-2.73 (m, 2H),2.26-2.21 (m, 2H), 2.01-1.89 (m, 2H), 1.39-1.33 (m, 7H), 0.82 (d, J=6.6Hz, 6H).

Example 47

Step 1. Synthesis of 47-1

To a solution of 9-3 (346 mg, 1 mmol) in chloroform (12 mL) at rt, wasadded potassium carbonate (552 mg, 4 mmol). After the reaction wascooled down to 0° C., a solution of thiophosgen (230 mg, 2 mmol) inchloroform (8 mL) was added dropwise. The reaction mixture was stirredat 0° C. for 3 hour. The solid was filtered and the filtrate wasconcentrated. The crude product was purified by prep.TLC plates(petroleum ether/ethyl acetate=10/1) to afford the desired product (180mg, 46% yield).

Step 2. Synthesis of 47-2

A solution of 47-1 (194 mg, 0.5 mmol) in acetonitrile (10 mL) and1,2-diaminobenzene (54 mg, 0.5 mmol) was stirred at room temperature for16 h. N,N-diisopropylethylamine (129 mg, 1 mmol) and HATU (285 mg, 0.75mmol) were added, and the reaction was stirred at room temperature foranother hour. The reaction was diluted with ethyl acetate (50 mL). Theorganic layer was washed with water (50 mL) and brine (50 mL), driedover sodium sulfate, filtered, and concentrated. The crude product waspurified by reversed-HPLC (acetonitrile/0.05% TFA.=10%-95%) to affordthe desired product (110 mg, 47% yield).

Step 3. Synthesis of 47

A solution of 47-2 (110 mg, 0.24 mmol) and lithium hydroxide (0.7 mL,0.7 mmol, 1 M aq.) in tetrahydrofuran/methanol (1.4 mL, v/v=1/1) wasstirred at 60° C. for 24 hour. The reaction was cooled down and the pHof the solution was adjusted to 6 with 1 N HCl. The reaction was dilutedwith ethyl acetate (50 mL). The organic layer was washed with water (50mL) and brine (50 mL), dried over sodium sulfate, filtered, andconcentrated. The residue was purified by reversed-HPLC(acetonitrile/0.02% ammonium hydroxide aq=10%-95%) to afford the desiredproduct (11.73 mg, 11% yield). LCMS (ES, m/z): 449.2 [M+H]^(|). HNMR(400 MHz, DMSO-d₆, ppm): δ 12.15-12.08 (m, 1H), 11.73 (s, 1H), 8.64 (s,1H), 8.23 (s, 1H), 7.30-7.16 (m, 3H), 6.97-6.87 (m 3H), 2.59-2.48 (m,6H), 1.78-1.56 (m, 8H), 0.86 (d, J=6.4 Hz, 12H).

Example 48

Step 1. Synthesis of 48-1

A solution of 9-3 (121 mg, 0.35 mmol), iodobenzene (143 mg, 0.7 mmol),Pd₂(dba)₃ (16 mg, 0.018 mmol), PCy₃ (10 mg, 0.035 mmol), and sodiumtert-butoxide (50 mg, 0.5 mmol) in toluene (5 mL) was stirred at 120° C.for 3 hour under microwave condition. Ethyl acetate (50 mL) was added,and the reaction was washed with water (50 mL) and brine (50 mL). Theorganic layer was dried over sodium sulfate, filtered, and concentrated.The residue was purified by pre-TLC (petroleum ether/ethyl acetate=10/1)to give the desired product (53 mg, 36% yield).

Step 2. Synthesis of 48

To a solution of 48-1 (53 mg, 0.125 mmol) in tetrahydrofuran/methanol (1mL, v/v=1/1) was added lithium hydroxide (0.5 mL, 0.5 mmol, 1N) at roomtemperature. The reaction mixture was stirred at 60° C. for 24 hour. Thereaction was cooled down and the pH of the solution was adjusted to 6with 1 N HCl. The reaction was diluted with ethyl acetate (50 mL). Theorganic layer was washed with water and brine, dried over sodiumsulfate, filtered, and concentrated. The residue was purified by pre-TLC(petroleum ether/ethyl acetate=7/1) to afford the desired product (40mg, 78% yield). LCMS (ES, m/z): 409.2 [M+H]⁺. HNMR (400 MHz, CD₃OD,ppm): δ 7.35 (d, J=2.0 Hz, 1H), 7.24-7.20 (m, 2H), 7.10-7.05 (m, 3H),6.87-6.84 (m 2H), 2.58-2.53 (m, 6H), 1.83-1.80 (m, 2H), 1.71-1.67 (m,6H), 0.87 (d, J=6.4 Hz, 12H).

Example 49

Step 1. Synthesis of 49-1

A solution of 9-3 (277 mg, 0.8 mmol), 2-bromopyrimidine (254 mg, 1.6mmol), Pd₂(dba)₃ (37 mg, 0.04 mmol), PCy₃ (22 mg, 0.08 mmol), and sodiumtert-butoxide (115 mg, 1.2 mmol) in toluene (5 mL) was stirred at 150°C. for 3 hour under microwave condition. Ethyl acetate (50 mL) wasadded, and the reaction was washed with water (50 mL) and brine (50 mL).The organic layer was dried over sodium sulfate, filtered, andconcentrated. The residue was purified by prep. TLC plates (petroleumether/ethyl acetate=10/1) to give the desired product.

Step 2. Synthesis of 49

To a solution of 49-1 (40 mg, 0.8 mmol) in tetrahydrofuran/methanol (4.8mL, v/v=1/1) was added lithium hydroxide (2.4 mL, 2.4 mmol, 1N) at roomtemperature. The reaction mixture was stirred at 60° C. for 24 hour. Thereaction was cooled down and the pH of the solution was adjusted to 6with 1 N HCl. The reaction was diluted with ethyl acetate (50 mL). Theorganic layer was washed with water and brine, dried over sodiumsulfate, filtered, and concentrated. The residue was purified by HPLC toafford the desired product (8.92 mg, 19% yield). LCMS (ES, m/z): 411.2[M+H]⁺. HNMR (400 MHz, CD₃OD, ppm): δ 8.59 (s, 1H), 8.44 (d, J=4.8 Hz,2H), 7.19 (d, J=8.4 Hz, 1H), 7.01 (d, J=8.0 Hz, 1H), 6.79 (t, J=4.8 Hz,1H), 2.65-2.58 (m, 6H), 1.93-1.91 (m, 2H), 1.74-1.65 (m, 6H), 0.91 (d,J=6.4 Hz, 12H).

Example 50

Step 1. Synthesis of 50-1

To a solution of 25-2 (500 mg, 1.4 mmol) in methanol (4 mL), was addedsulphuric acid (2 mL) at 0° C. The reaction was stirred at 80° C. for 16hours. The mixture was extracted with ethyl acetate (50 mL) and washedwith sodium bicarbonate solution (100 mL). The organic layer was driedover sodium sulfate, filtered, and concentrated. The residual waspurified by chromatography on a silica gel column (petroleum ether/ethylacetate=4/1) to afford the desired product (130 mg, 23% yield).

Step 2. Synthesis of 50-2

To a solution of 50-1 (80 mg, 0.2 mmol) in methanol (5 mL) was addedpalladium on carbon (40 mg). The reaction was stirred for 2 hours atroom temperature under hydrogen. The mixture was filtered and thefiltrate was concentrated to afford the desired product (50 mg, 69%yield).

Step 3. Synthesis of 50-3

To a solution of 50-2 (50 mg, 0.14 mmol) in dichloromethane (5 mL), wasadded triethylamine (43 mg, 0.42 mmol) and then isobutyryl chloride (30mg, 0.28 mmol). The reaction was stirred at room temperature for16hours. The mixture was extracted with ethyl acetate (50 mL) and washedwith water (50 mL). The organic layer was dried over sodium sulfate,filtered, and concentrated. The residual was purified by pre-TLC(petroleum ether/ethyl acetate=4/1) to afford the desired product (30mg, 50% yield).

Step 4. Synthesis of 50

To a solution of 50-3 (30 mg, 0.07 mmol) in methanol (1 mL) andtetrahydrofuran (1 mL), was added lithium hydroxide solution (1 mL, 1N).The reaction was stirred at 60° C. for 16 hours. The mixture wasacidified with hydrochloric acid (1 N) and then extracted with ethylacetate (50 mL). The organic layer was dried over sodium sulfate,filtered, and concentrated. The residual was purified by pre-HPLC toafford the desired product as a white solid (10 mg, 34% yield). LCMS(ES, m/z): 417.2 [M+H]⁺. HNMR (400 MHz, DMSO-d₆, ppm): δ 8.83 (s, 1H),8.24 (d, J=2.0 Hz, 1H), 7.24 (d, J=8.4 Hz, 1H), 6.92 (dd, J1=8.4 Hz,J2=2.0 Hz, 1H), 3.82-3.79 (m, 2H), 3.17 (t, J=11.2 Hz, 2H), 2.80-2.73(m, 3H), 2.68-2.61 (m, 2H), 2.59-2.54 (m, 1H), 2.37-2.29 (m,2H),1.88-1.86 (m, 1H), 1.77-1.73 (m, 1H), 1.62-1.59 (m, 2H), 1.50-1.42(m, 2H), 1.28-1.23 (m, 1H),1.11 (d, J=6.8 Hz, 6H), 0.79 (d, J=6.4 Hz,6H).

Example 51

Step 1. Synthesis of 78-1

To a stirred solution of 50-2 (105 mg, 0.29 mmol) in 1,2-Dichloroethane(5 mL), were added cyclopentanone (90 mg, 1.07 mmol) and trifluoroaceticacid (90 mg, 0.79 mmol). The mixture was stirred at room temperature for1 h, then tetramethylammonium triacetoxyborohydride (150 mg, 0.57 mmol)was added. The mixture was stirred at 60° C. for 16 h. After cooleddown, the reaction mixture was extracted with ethyl acetate (50 mL). Theorganic phase was washed with aqueous NaHCO₃ (20 mL) and brine (10 mL),dried over anhydrous sodium sulfate, and concentrated under vacuum. Theresidue was purified by pre-TLC (eluent: petroleum ether:ethylacetate=4:1) to afford the desired product (50 mg, 40% yield).

Step 2. Synthesis of 78

To a solution of 78-1 (50 mg, 0.12 mmol) in tetrahydrofuran (1.5 mL) andmethyl alcohol (1.5 mL), was added lithium hydroxide (1 M, 1.5, mL, 1.5mmol). The mixture was stirred at 60° C. for 3 h. After cooled down, thereaction was acidified to pH=4 with hydrochloric acid (1N), andextracted with EtOAc. The organic phase was washed with brine (10 mL),dried over anhydrous sodium sulfate, and concentrated under vacuum toafford the desired product (22 mg, 44% yield). LCMS (ES, m/z): 415.3[M+H]⁺. ¹HNMR: (400 MHz, CD₃OD, ppm): δ 7.00 (d, J=8.0 Hz, 1H),6.59-6.54 (m, 2H), 3.91(d, J=11.2 Hz, 2H), 3.79-3.77 (m, 1H),3.32-3.26(m, 1H), 3.26-3.21(m, 1H), 2.98 (d, J=9.6 Hz, 1H),2.78-2.71 (m,3H), 2.56-2.41 (m, 3H), 2.00-1.92 (m, 3H), 1.86-1.37 (m, 12H), 0.82(dd,J1=24.8 Hz, J2=6.4 Hz, 6H).

Example 52

Step 1. Synthesis of 83-1

To a solution of 2-chloro-5-pyridineacetonitrile (14.3 g, 94 mmol) indimethylformamide (120 mL) at 0° C., was added sodium hydride (8.6 g,216 mmol, 60% in oil) portion-wise over 20 minutes. The mixture wasstirred for a further 20 minutes and 1,3-dibromopropane (20 g, 98.7mmol) was added. The reaction mixture was warmed to room temperature andstirred for 2 h. The reaction was quenched by water (50 mL). Ethylacetate (200 mL) was added and the organic phase was washed with water(100 mL) and brine (100 mL). The organic layer was dried over sodiumsulfate, filtered, and concentrated. The crude product was purified bychromatography on a silica gel column (petroleum ether to petroleumether/ethyl acetate=3/1) to afford the desired product (9.4 g, 52%yield).

Step 2. Synthesis of 83-2

To a solution of potassium hydroxide (840 mg, 15 mmol) in water/methanol(6 mL, v/v=1/2) at room temperature, were added sodium methoxide (3.6 g,20 mmol, 30% in methanol) and 83-1 (960 mg, 5 mmol). The reaction wasthen heated to 100° C. for 48 h. After cooled to 0° C., the mixture wasadjusted to pH-5 with 1N HCl. The mixture was diluted with water (50mL), and extracted with dichloromethane (50 mL×4). The organic layer wasdried over sodium sulfate, filtered, and concentrated to afford thedesired product (950 mg, 92% yield).

Step 3. Synthesis of 83-3

To a solution of 83-2 (350 mg, 1.7 mmol) in concentrated sulfuric acid(2 mL) at 0° C., was added concentrated nitric acid (1 mL) dropwise. Thereaction was heated to 50° C. for 16 h. After cooled to roomtemperature, the mixture was poured into ice water, and the pH value ofthe misture was adjusted to 4 with 50% sodium hydroxide at 0° C. Themixture was extracted with dichloromethane (50 mL×3). The organic layerwas dried over sodium sulfate, filtered, and concentrated. The residuewas purified by reversed HPLC (MeCN/0.05% TFA aq=5%-95%) to afford thedesired product (180 mg, 42% yield).

Step 4. Synthesis of 83-4

To a solution of 83-3 (504 mg, 2 mmol) in thionyl chloride (3 mL) at 0°C., was added dimethylformamide (292 mg, 4 mmol) dropwise. The reactionwas heated to 80° C. for 16 h, and then concentrated. The residue wasdissolved in dichloromethane (5 mL), and then methanol (1 mL) was addedat 0° C. The mixture was stirred for 0.5 h at room temperature. Themixture was concentrated and purified by reversed HPLC (MeCN/0.05% TFAaq=5%˜95%) to afford the desired product (400 mg, 74% yield).

Step 5. Synthesis of 83-5

To a solution of 83-4 (135 mg, 0.5 mmol) in N-methyl-2-pyrrolidone (2mL), were added N,N-diisopropylethylamine (97 mg, 0.75 mmol) anddiisobutylamine (97 mg, 0.75 mmol). The reaction was stirred at 90° C.for 16 h. The mixture was purified by reversed HPLC directly (MeCN/0.05%TFA aq=5%˜95%) to afford the desired product (168 mg, 93% yield).

Step 6. Synthesis of 83-6

To a solution of 83-5 (554 mg, 1.5 mmol) in methanol (10 mL) was addedpalladium 10% on carbon (110 mg). The reaction was stirred for 2 hour atroom temperature under hydrogen. The mixture was filtered and thefiltrate was concentrated. The crude product was purified bychromatography on a silica gel column (petroleum ether to petroleumether/ethyl acetate=5/1) to afford the desired product (400 mg, 80%yield).

Step 7. Synthesis of 83-7

To a solution of 83-6 (80 mg, 0.24 mmol) in tetrahydrofuran (10 mL) at0° C., were added triethylamine (50 mg, 0.48 mmol) and2,4-difluoro-1-isocyanatobenzene (75 mg, 0.48 mmol). The reaction wasstirred at room temperature for 2 h. The mixture was extracted withethyl acetate (50 mL) and washed with water (50 mL). The organic phasewas concentrated and purified by pre-TLC (petroleum ether/ethylacetate=6/1) to afford the desired product (80 mg, 68% yield).

Step 8. Synthesis of 83

To a solution of 83-7 (80 mg, 0.16 mmol) in methanol (2 mL) andtetrahydrofuran (2 mL), was added lithium hydroxide solution(2 mL, 1M, 2mmol). The reaction was stirred for 5 hour at 60° C. The mixture wasacidized with hydrochloric acid (1 N) and extracted with ethyl acetate(50 mL). The organic layer was dried over sodium sulfate, filtered, andconcentrated. The residual was purified by Pre-TLC (eluent: petroleumether:ethyl acetate=1:1) to afford the desired product (65.2 mg, whitesolid, 86% yield). LCMS (ES, m/z): 475.3 [M+H]⁺. HNMR (400 MHz, DMSO-d₆,ppm): δ 12.41 (brs, 1H), 9.28 (s, 1H), 8.05-7.94 (m, 3H), 7.86 (d, J=2.0Hz, 1H), 7.32-7.26 (m, 1H), 7.03-6.99 (m, 1H), 2.96 (d, J=6.8 Hz, 4H),2.67-2.60 (m, 2H), 2.38-2.31(m, 2H), 1.95-1.86 (m, 1H),1.80-1.75 (m,1H), 1.73-1.66(m, 2H), 0.76 (d, J=6.4 Hz, 12H).

Example 53

Step 1. Synthesis of 120-1

To a solution of 83-4 (1.7 g, 6.3 mmol) in dimethyl sulfoxide (30 mL)was added N-ethyloxan-4-amine (1.6 g, 12.6 mmol) andN,N-diisopropylethylamine (1.6 g, 12.6 mmol). The reaction was stirredfor 16 h at 90° C. After cooled down, the reaction was diluted withethyl acetate (100 mL), and washed with water (100 mL) and brine (100mL). The organic layer was dried over sodium sulfate, filtered, andconcentrated. The residue was purified by chromatography on a silica gelcolumn (petroleum ether to petroleum ether/ethyl acetate=4/1) to givethe desired product (1.6 g, 69% yield) as a yellow oil.

Step 2. Synthesis of 120-2

To a solution of 120-1 (1.6 g, 4.4 mmol) in methanol (50 mL) was added10% palladium on carbon (320 mg). The reaction was stirred for 2 h atroom temperature under hydrogen. The mixture was filtered, andconcentrated. The crude product was purified by chromatography on asilica gel column (petroleum ether to petroleum ether/ethyl acetate=1/1)to give the desired product (950 mg, 65% yield) as a light grey oil.

Step 3. Synthesis of 120-3

To a mixture of 120-2 (80 mg, 0.24 mmol), 1-chloro-4-iodobenzene (114mg, 0.48 mmol) and sodium tert-butoxide (46 mg, 0.48 mmol) inmethylbenzene (4 mL), was added tris(dibenzylideneacetone)dipalladium(0)(11 mg, 0.012 mmol) and2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl (11 mg, 0.024 mmol).The mixture was stirred under N₂ at 120° C. in microwave for 30 min.After the completion of the reaction, water (10 mL) was added, and thereaction mixture was extracted with ethyl acetate (20 mL). The organicphase was washed with brine (10 mL), dried over sodium sulfate, andconcentrated. The crude product was purified by preparative TLC (eluent:petroleum ether/ethyl acetate=1/1) to give the desired product (45 mg,42% yield) as a yellow gel.

Step 4. Synthesis of 120

To a mixture of 120-3 (45 mg, 0.1 mmol) in tetrahydrofuran (1.5 mL) andmethyl alcohol (1.5 mL) was added lithium hydroxide (1M, 1.5 mL), themixture was stirred at 60° C. for 3 h After the completion of thereaction, the mixture was acidified to pH=3 with hydrochloric acid (1M),and extracted with ethyl acetate (20 mL) The organic phase was washedwith brine (10 mL), dried over sodium sulfate, and concentrated. Thecrude product was purified by preparative TLC (eluent:dichloromethane/methyl alcohol=10/1) to give the desired product (32 mg,73% yield) as a white solid.

Example 54: Inhibition of Kynurenine Production in HeLa Cells

The effect of compounds described herein on the inhibition of kynurenineproduction in HeLa cells (derived from human cervical cancer) wasdetermined. Exemplary results are shown in Table 2. HeLa cells wereseeded into a 96-well culture plate at a density of 5×10³ per well inRPMI1640/phenol red free media (from GIBCO) with 2 mM L-glutamine and10% fetal bovine serum (FBS, from GIBCO) and grown overnight in a 37° C.incubator with 5% CO₂. Twenty-four hours later, human IFN-γ (from GIBCO)(final concentration 50 ng/mL) and test compound solutions (seriallydiluted to different wells) were added to each well with a final volumeof 200 uL per well. Forty-eight hours after incubation with compounds,140 uL supernatant was taken from each well and was transferred to a new96-well plate. Ten microliters of 6.1 N trichloroacetic acid were addedinto each well, mixed and incubated at 50° C. for 30 minutes. Thereaction mixture was then centrifuged for 10 minutes at 2500 rpm and 100uL of the supernatant per well was transferred to another 96 well plateand mixed with 100 uL of 2% (w/v) p-dimethylaminobenzaldehyde in aceticacid. The yellow color derived from kynurenine was measured at 480 nmusing a SPECTRAmax i3 reader. Each compound concentration was done intriplicates and compound IC50 value was calculated using nonlinearregression using Graphpad Prism 5.0.

The inhibitory activity of representative compounds described herein,compared with another IDO inhibitor, such as INCB-24360, Controls 1 and2 are shown in Table 2.

TABLE 2 Inhibitory Activity of Representative Compounds Compound IC₅₀(nM) Compound IC₅₀ (nM) INCB-24360 6.9 — — Control 1* 0.8 Control 2** 3 1 129.6  2 9.1  3A 9.1  3B 0.6  4 14.9  5A 19.7  5b 0.7  6 8.5  7 6.3 8 47.0  9 2.2  10 0.9  11 0.9  12 0.5  13 0.6  14 0.5  15 1.4  16 1.5 17 0.8  18 6.6  19 1.0  20 0.5  21 0.6  22 2.1  23 61.5  24 2.2  25 0.6 27 5.7  28 >316  29 4.0  30 1.0  31 11.8  32 0.8  33 48  34 7.7  35 1.9 36 2.8  37 19.9  41 6.4  43 134  45 78  47 5.6  48 8.4  49 >316 50 >316  51 2.3  52 0.3  53 1.0  54 0.6  55 0.3  56 0.2  57 0.2  59A12.7  59B 0.1  60A 33  60B 2.8  61A 0.3  61B 0.3  62A 1.4  62B 0.2  63A2.5  63B −0.6  64A 4.2  64B 0.2  65A 0.8  65B 12  68A 0.4  68B 0.7  693.9  70A 0.4  70B 0.4  71A 0.3  71B 0.9  72 0.2  73 0.4  74 1.9  75 0.3 76 1.1  77 3  78 13.9  80 29  83 5.4  84 0.4  85 19  86 0.3  87 6.5  881.7  89 6.3  90 33  91 0.3  92 0.2  93 0.3  94 0.2  95 0.4  96 0.4  972.4  98 2.8  99 3.9 100 3.5 101 0.2 102 0.2 103 20 104 1.8 105 0.3 1060.4 107 0.4 108 0.3 109 >316 110 1.0 111 0.8 112 0.2 113 0.4 114 25 1150.1 116 0.5 117 0.9 118 0.2 119 1.7 120 0.1 121 4.1 122 2.3 123 0.3 12411.3 125 0.5 126 7.5 127 22 128 9.3 *Control 1:3-(3-(3-(2,4-difluorophenyl)ureido)-4-(diisobutylamino)phenyl)-4,4,4-trifluorobutanoicacid. See Example 30 of WO2014/150646 **Control 2:(1R,2S)-2-(4-(diisobutylamino)-3-(3-(3-methylisoxazol-5-yl)ureido)phenyl)cyclopropanecarboxylicacid. See Example 30 of WO2014/150677

Example 55: Inhibition of Kynurenine Production in SKOV-3 Cells

The effect of compounds described herein on the inhibition of kynurenineproduction in SKOV-3 cells (derived from human ovarian cancer) wasdetermined using a similar experimental procedure as described inExample A. Exemplary results are shown in FIG. 1.

The assay was performed similarly as described in Example A, except theSKOV-3 cells were grown in DMEM media with 10% FBS. FIG. 1 shows theIC₅₀ for INCB-24360 and compound 9 were determined at 10.2 nM and 7.4nM, respectively. The structure of compound 9 is shown below:

Example 56: Inhibition of LPS Induced Plasma Kynurenine in Mice

The effect of compounds described herein on the inhibition oflipopolysaccharide (LPS)-induced plasma kynurenine in mouse wasdetermined. Exemplary results are shown in FIG. 2. Female Balb/c mouse(˜20 g, obtained from Vital River Laboratory Animal Co. LTD) was treatedwith either vehicle control (saline) or 5 mg/kg LPS via intraperitonealinjection, followed by an oral dose of 30 mpk compound 9 within 5minutes of LPS injection. Blood samples (500 uL) were collected intoK₂EDTA tube via retro-orbital puncture at 12 and 24 hrs (terminalbleeding) after treatment with LPS or LPS plus compound 9. For vehiclecontrol group, plasma samples were collected at 24 hour post dose. Bloodsamples were put on ice after collection and centrifuged at 4° C. (2000g, 5 minutes) immediately after collection to obtain the plasma. Plasmakynurenine level was determined by LC-MS/MS analysis. Each groupcontains 3 mice and mean plasma kynurenine level was plotted in FIG. 2.FIG. 2 shows LPS induced mouse plasma kynurenine level compared to thebaseline (vehicle control group) and simultaneous treatment of LPS withIDO inhibitor compound 9 reduced the plasma kynurenine to the levelbelow the baseline, with 72% drop and 85% drop at 12 and 24 hour timepoints, respectively, compare to the LPS treatment alone.

Example 57: Human Hepatocyte Clearance Study

The in vitro human hepatocyte clearance of compounds described here wasstudied using pooled human hepatocytes purchased from BioreclamationIVT(Westbury, N.Y., Cat #X008001, Lot #TQJ). The assay was conductedaccording to manufacture's instruction. Briefly, 10 mM stock solutionsof test compounds and positive control (Verapamil) were prepared in 100%DMSO. Thawing media (50 mL) used in the study consists of: 31 mLWilliams E medium (GIBCO Cat #12551-032); 15 mL isotonic percoll (GEHealthcare Cat #17-0891-09); 500 uL 100× GlutaMax (GIBCO Cat #35050);750 uL HEPES (GIBCO Cat #15630-080); 2.5 mL FBS (Corning Cat#35-076-CVR); 50 uL human insulin (GIBCO Cat #12585-014) and 5 uLdexamethasone (NICPBP). Incubation media is made of Williams E mediumsupplemented with 1× GlutaMax. Both thawing medium and incubation medium(serum-free) were placed in a 37° C. water bath for at least 15 minutesprior to use. Compound stock solutions were diluted to 100 μM bycombining 198 μL of 50% acetonitrile/50% water and 2 μL of 10 mM stocksolution. Verapamil was use as positive control in the assay. Vials ofcryopreserved hepatocytes were removed from storage and thawed in a 37°C. water bath with gentle shaking. Contents of the vial were poured intothe 50 mL thawing medium conical tube. Vials were centrifuged at 100 gfor 10 minutes at room temperature. Thawing medium was aspirated andhepatocytes were re-suspended with serum-free incubation medium to yield˜1.5 ×10⁶ cells/mL. Hepatocyte viability and density were counted usinga Trypan Blue exclusion, and then cells were diluted with serum-freeincubation medium to a working cell density of 0.5×10⁶ viable cells/mL.Then, a portion of the hepatocytes at 0.5 ×10⁶ viable cells/mL wasboiled for 5 minutes prior to adding to the plate as negative control toeliminate the enzymatic activity so that little or no substrate turnovershould be observed. The boiled hepatocytes were used to prepare negativesamples. Aliquots of 198 μL hepatocytes were dispensed into each well ofa 96-well non-coated plate. The plate was placed in the incubator on anorbital shaker at 500 rpm for approximately 10 minutes. Aliquots of 2 μLof the 100 μM test compound or positive control were added intorespective wells of the non-coated 96-well plate to start the reaction.This assay was performed in duplicate. The plate was incubated in theincubator on an orbital shaker at 500 rpm for the designated timepoints. Twenty-five microliter of contents were transferred and mixedwith 6 volumes (150 μL) of cold acetonitrile with IS (200 nM imipramine,200 nM labetalol and 200 nM diclofenac) to terminate the reaction attime points of 0, 15, 30, 60, 90 and 120 minutes. Samples werecentrifuged at 3,220 g for 25 minutes and aliquots of 150 μL of thesupernatants were used for LC-MS/MS analysis. For data analysis, allcalculations were carried out using Microsoft Excel. Peak areas weredetermined from extracted ion chromatograms. The in vitro half-life(t_(1/2)) of parent compound was determined by regression analysis ofthe percent parent disappearance vs. time curve. The in vitro half-life(in vitro t_(1/2)) was determined from the slope value: in vitrot_(1/2)=0.693/k. Conversion of the in vitro t_(1/2) (in minutes) intothe scale-up unbound intrinsic clearance (Scaled-up unbound CL_(int), inmL/min/kg) was done using the following equation (mean of duplicatedeterminations): Scaled-up unbound CL_(int)=kV/N×scaling factor, whereV=incubation volume (0.5 mL); N=number of hepatocytes per well (0.25×10⁶cells). Scaling factors for in vivo intrinsic clearance predictionusing human hepatocytes are listed as: liver weight (g liver/kg bodyweight): 25.7; hepatocyte concentration (10⁶ cells/g liver): 99; scalingfactor: 2544.3.

TABLE 3 Human Hepatocyte Clearance of Exemplary Compounds HumanHepatocyte Human In Human In vitro Human Remaining vitro Cl_(int)Scale-up Percentage @ T_(1/2) (μL/min/10⁶ Cl_(int) Compound 120 min (%)(min) cells) (mL/min/kg) INCB- 35 73 19 48 24360 Control 1* 76 336 4.111  3B 98 2111 0.7 1.8  9 79 423 3 10  16 101 1882 0.7 1.8  25 89 9021.5 3.9  48 105 1733 0.8 2  75 88 534 2.6 6.6  84 80 623 2.2 5.7  86 75268 5.2 13  91 92 1060 1.3 3.3 105 81 275 5.1 13 106 69 198 7 18 107 76252 5.5 14 110 71 216 6.4 16 111 63 179 7.7 20 115 83 381 3.6 9.3 117 932125 0.7 1.7 118 85 416 3.3 8.5 120 94 1023 1.4 3.5 123 100 964 1.4 3.7125 97 1593 0.9 2.2 *Control 1:3-(3-(3-(2,4-difluorophenyl)ureido)-4-(diisobutylamino)phenyl)-4,4,4-trifluorobutanoicacid. See Example 30 of WO2014/150646.

Example 58: Inhibition of IDO in Human Whole Blood Assay

About 50-80 mL of human blood was collected in a tube with sodiumheparin from each healthy donor. The tube containing human blood waskept on a rotator till ready for use. The following solutions wereprepared for the assay: 10× LPS (Sigma #L2630) solution at 1000 ng/ml inRPMI media (with 10 mM HEPES), 10× INF-gamma (R&D Systems #CA31639)solution in RPMI media (with 10 mM HEPES), 75× compound/inhibitorsolution in 100% DMSO. The entire content of human blood was poured fromthe tube into a reservoir dish and ˜120 uL blood was transferred fromthe dish into each well of a 96-well plate (polypropylene U bottom clearplate). Then 15 uL each of 10× LPS and 10× INF-gamma, 2 uL of 75×compound solution were added into each well. The 96-well plate wasgently rotated to mix the solutions and was then covered with abreathable membrane. The plate is transferred to cell culture incubator(37° C. with 5% CO₂). After 18 hr of incubation, the plate was spun at1800 rpm for 10 min with no brake to separate plasma from blood cells.Sixty microliter of plasma was gently removed without disturbing thecells from each well. The kynurenine and tryptophan in the plasma areanalyzed by LC-MS method.

FIG. 3, panel A shows the percentage inhibition of kynurenine/tryptophanratio by compound 84 and compound INCB-24360, respectively, as afunction of the concentration of each compound. FIG. 3, panel B showsthe percentage inhibition of kynurenine by compound 84 and compoundINCB-24360, respectively, as a function of the concentration of eachcompound.

Example 59: T Cells and HeLa Cells Co-Culture Assay

HeLa cells were seeded into 96-well plate (5000 cells per well in 100 μLof cell growth media DMEM with 10% FBS and 1% pen/strep) and incubatedat 37° C. with 5% CO₂. After overnight incubation, 200 μL of INF-gamma(50 ng/ml in frowth media) was added to the plate and returned toincubator for another 48 hr. SepMate™-50 centrifuge tube was used toisolate PBMC from human donor according to manufacture's instruction(Stemcell). The CD3 T cell was then isolated from the PBMC using EasySepHuman T cell isolation kit (Stemcell). Wash the 96-well plat twice with200 μL of co-culture media (RPMI-1640+10% FBS+1% Pen/strep). Adjust theCD3 T cells density to 5×10⁵ cells/ml with high dose anti-CD3/CD28 beadsand co-culture medium (RPMI-1640+10% FBS+1% Pen/strep) and seed 200μL/well into 96-well plate. Compound at different concentration wasadded to each well and the plate was incubated for a further 72 hr.Level of INF-gamma in the co-culture media (100 μL) was analyzed usingthe Human IFN-gamma ELISA Ready-SET-GO kit from eBioscience. The resultsobtained from this example are shown in FIG. 4.

Equivalents and Scope

In the claims, articles such as “a,” “an,” and “the” may mean one ormore than one unless indicated to the contrary or otherwise evident fromthe context. Claims or descriptions that include “or” between one ormore members of a group are considered satisfied if one, more than one,or all of the group members are present in, employed in, or otherwiserelevant to a given product or process unless indicated to the contraryor otherwise evident from the context. The invention includesembodiments in which exactly one member of the group is present in,employed in, or otherwise relevant to a given product or process. Theinvention includes embodiments in which more than one, or all of thegroup members are present in, employed in, or otherwise relevant to agiven product or process.

Furthermore, the invention encompasses all variations, combinations, andpermutations in which one or more limitations, elements, clauses, anddescriptive terms from one or more of the listed claims is introducedinto another claim. For example, any claim that is dependent on anotherclaim can be modified to include one or more limitations found in anyother claim that is dependent on the same base claim. Where elements arepresented as lists, e.g., in Markush group format, each subgroup of theelements is also disclosed, and any element(s) can be removed from thegroup. It should it be understood that, in general, where the invention,or aspects of the invention, is/are referred to as comprising particularelements and/or features, certain embodiments of the invention oraspects of the invention consist, or consist essentially of, suchelements and/or features. For purposes of simplicity, those embodimentshave not been specifically set forth in haec verba herein. It is alsonoted that the terms “comprising” and “containing” are intended to beopen and permits the inclusion of additional elements or steps. Whereranges are given, endpoints are included. Furthermore, unless otherwiseindicated or otherwise evident from the context and understanding of oneof ordinary skill in the art, values that are expressed as ranges canassume any specific value or sub-range within the stated ranges indifferent embodiments of the invention, to the tenth of the unit of thelower limit of the range, unless the context clearly dictates otherwise.

This application refers to various issued patents, published patentapplications, journal articles, and other publications, all of which areincorporated herein by reference. If there is a conflict between any ofthe incorporated references and the instant specification, thespecification shall control. In addition, any particular embodiment ofthe present invention that falls within the prior art may be explicitlyexcluded from any one or more of the claims. Because such embodimentsare deemed to be known to one of ordinary skill in the art, they may beexcluded even if the exclusion is not set forth explicitly herein. Anyparticular embodiment of the invention can be excluded from any claim,for any reason, whether or not related to the existence of prior art.

Those skilled in the art will recognize or be able to ascertain using nomore than routine experimentation many equivalents to the specificembodiments described herein. The scope of the present embodimentsdescribed herein is not intended to be limited to the above Description,but rather is as set forth in the appended claims. Those of ordinaryskill in the art will appreciate that various changes and modificationsto this description may be made without departing from the spirit orscope of the present invention, as defined in the following claims.

1. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein: W is —O—, —S—,or a bond; Q is —C(═O)NH— or a bond; Y is —CR⁸═ or —N═, as valencypermits; R¹ is —C(═O)OH, —C(═O)OR¹⁰, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted heteroaryl, —NHSO₂R⁹,—C(═O)NHSO₂R⁹, —C(═O)NHC(═O)OR¹⁰, or —SO₂NHC(═O)R¹⁰; R² and R³ are eachindependently hydrogen, halogen, substituted or unsubstituted C₁-C₆alkyl, substituted or unsubstituted C₁-C₆ alkoxy, or R² and R³ arejoined to form a substituted or unsubstituted 3- to 8-memberedcarbocyclic ring, or substituted or unsubstituted 3- to 8-memberedheterocyclic ring; R⁴ and R⁵ are each independently hydrogen,substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstitutedC₂-C₆ alkenyl, substituted or unsubstituted C₅-C₈ cycloalkenyl,substituted or unsubstituted C₂-C₁₀ alkynyl, substituted orunsubstituted C₁-C₆ alkoxy, substituted or unsubstituted C₃-C₈cycloalkyl, substituted or unsubstituted 3- to 12-membered heterocyclyl,substituted or unsubstituted 5- to 6-membered monocyclic heteroaryl,substituted or unsubstituted 8- to 10-membered bicyclic heteroaryl,substituted or unsubstituted aryl, or arylsulfonyl; or R⁴ and R⁵ arejoined together with the N they are attached to to form optionallysubstituted, monocyclic or bicyclic, heterocyclyl; R⁶ is substituted orunsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₃-C₈cycloalkyl; substituted or unsubstituted C₂-C₆ alkenyl, substituted orunsubstituted C₂-C₆ alkynyl, substituted or unsubstituted C₅-C₈cycloalkenyl, substituted or unsubstituted aryl, substituted orunsubstituted 4- to 7-membered monocyclic heterocyclyl, substituted orunsubstituted 7- to 10-membered bicyclic heterocyclyl, substituted orunsubstituted 5- to 6-membered monocyclic heteroaryl, substituted orunsubstituted 8- to 10-membered bicyclic heteroaryl, substituted orunsubstituted C₁-C₆ alkoxy, substituted or unsubstituted aryloxy, or—C(═O)R⁷; R⁷ is hydrogen, substituted or unsubstituted C₁-C₆ alkyl, orsubstituted or unsubstituted aryl; R⁸ is hydrogen, halogen, —CN, —OH,substituted or unsubstituted C₁-C₆ alkyl, or substituted orunsubstituted C₁-C₆ alkoxy; and R⁹ and R¹⁰ are each independentlyhydrogen, substituted or unsubstituted C₁-C₆ alkyl, or substituted orunsubstituted C₂-C₆ alkenyl.
 2. The compound of claim 1, wherein thecompound is of Formula (II):

or a pharmaceutically acceptable salt thereof. 3-6. (canceled)
 7. Thecompound of claim 1, wherein R¹ is: —C(═O)OH or


8. (canceled)
 9. (canceled)
 10. The compound of claim 1, wherein R² andR³ are joined to form a substituted or unsubstituted 3- to 6-memberedcarbocyclic ring, or substituted or unsubstituted 3- to 8-memberedheterocyclic ring.
 11. The compound of claim 1, wherein R² and R³ arejoined to form a substituted or unsubstituted cyclopropyl, substitutedor unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl,or substituted or unsubstituted cyclohexyl ring.
 12. (canceled) 13.(canceled)
 14. The compound of claim 1, wherein R⁴ and R⁵ are eachindependently substituted or unsubstituted C₁-C₆ alkyl, substituted orunsubstituted C₃-C₈ cycloalkyl, or substituted or unsubstituted 3- to12-membered heterocyclyl.
 15. The compound of claim 14, wherein R⁴ andR⁵ are each independently of the formula:

wherein R is substituted or unsubstituted C₁-C₆ alkyl. 16-20. (canceled)21. The compound of claim 1, wherein R⁶ is of the formula:

wherein R^(6A) is hydrogen, substituted or unsubstituted C₁-C₆ alkyl,halogen, —CN, —OR^(6a), or substituted or unsubstituted sulfonyl group;wherein R^(6a) is hydrogen, or substituted or unsubstituted C₁-C₆ alkyl;and k is 0, 1, or
 2. 22. The compound of claim 1, wherein R⁶ is of theformula:

23-25. (canceled)
 26. The compound of claim 1, wherein the compound is:

or a pharmaceutically acceptable salt thereof. 27-30. (canceled)
 31. Thecompound of claim 1, wherein the compound is:

or a pharmaceutically acceptable salt thereof.
 32. A pharmaceuticalcomposition comprising a compound of claim 1, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable excipient.33. A method of treating a disease associated with IDO, the methodcomprising administering to a subject in need thereof an effectiveamount of a compound of claim 1, or a pharmaceutically acceptable saltthereof, or a pharmaceutical composition comprising an effective amountof a compound of claim 1 or a pharmaceutically acceptable salt thereof.34. The method of claim 33, wherein the disease associated with IDO iscancer.
 35. The method of claim 33, wherein the disease associated withIDO is cancer, which is selected from the group consisting of lungcancer, breast cancer, prostate cancer, ovarian cancer, endometrialcancer, cervical cancer, bladder cancer, head and neck cancer, renalcell carcinoma, esophageal cancer, pancreatic cancer, brain cancer,cancers of the gastrointestinal tract, liver cancer, leukemia, lymphoma,melanoma, multiple myeloma, Ewing's sarcoma, and osteosarcoma.
 36. Themethod of claim 34, further comprising treating the subject with anadditional anti-cancer therapy.
 37. The method of claim 36, wherein theadditional anti-cancer therapy is immunotherapy, radiation therapy,chemotherapy, cell therapy, or surgery.
 38. The method of claim 36,wherein the additional anti-cancer therapy involves an anti-canceragent.
 39. The method of claim 33, wherein the disease associated withIDO is an infectious disease.
 40. The method of claim 39, wherein theinfectious disease is a viral infection and the subject is furthertreated with an additional anti-viral therapy.
 41. The method of claim40, wherein the additional anti-viral therapy involves an additionalanti-viral agent or anti-viral vaccine.
 42. (canceled)